Epinephrine spray formulations

ABSTRACT

The present invention is directed to epinephrine spray formulations. The present invention is further directed to methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatments.

FIELD OF THE INVENTION

The present invention is directed to epinephrine spray formulations. Thepresent invention is further directed to methods of treating anaphylaxisby administering epinephrine spray formulations to subjects in need ofsuch treatments.

BACKGROUND OF THE INVENTION

Epinephrine (i.e. adrenaline) is a catecholamine with the followingchemical structure:

Epinephrine stimulates the alpha- and beta-adrenergic receptors of thesympathetic nervous system. Epinephrine binds to these adrenergicreceptors leading to relief of many life-threatening symptoms ofanaphylaxis including: relaxation of the smooth muscle in the bronchi ofthe lungs opening up the constricted airways; constriction of the bloodvessels leading to decreased swelling of the tongue and throat andincreased blood pressure; and finally, increased heart rate preventingor reversing cardiovascular collapse.

Epinephrine is commercially available as an injection (Adrenalin® atrademark of and available from Par Sterile Products, LLC) and anauto-injector (EpiPen® a trademark of and available from Mylan, Inc. andAuvi-Q® a trademark of and available from Sanofi Corporation).Epinephrine was previously available as a nasal spray (Adrenalin®) andan aerosol spray (Primatene® Mist trademark of ArmstrongPharmaceuticals, Inc.). Racepinephrine is commercially available as a2.25% oral inhalation solution for use in nebulizers (S2® is availablefrom Nephron Pharmaceuticals, Inc.). Epinephrine differs fromracepinephrine in that epinephrine consists of only the L-isomer andracepinephrine is a 50/50 mixture of both the L- and D-isomers.

U.S. Pat. No. 8,628,805 is directed to a stable liquidadrenaline/bisulfite composition wherein the molar ratio of adrenalineto bisulfite is 1.31-2.20:1. U.S. Patent Application Publication No.2012/0322884 A1 is directed to epinephrine nanoparticles, which can beincorporated into sublingual tablets. U.S. Patent ApplicationPublication No. 2007/0202163 A1 is directed to epinephrine tablets forsublingual administration, which contain between 12% and 48%epinephrine. World Intellectual Property Organization (“W.I.P.O.”)Publication No. 2014/127018 A1 is directed to a stable aqueousepinephrine formulation that requires cyclodextrin. W.I.P.O. PublicationNo. 2014/057365 A1 is directed to an injectable epinephrine formulation.

While there are various epinephrine formulations currently available,there remains a need in the art for a quick-onset spray formulation.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to epinephrine sprayformulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof, preferably the salt is selected from the group        consisting of citrate, hydrochloride, halide, sulfate,        phosphate, acetate, maleate, succinate, ascorbate, carbonate,        mesylate and lactate;    -   from about 1% w/w to about 80% w/w water, preferably from about        5% to about 77% w/w, more preferably from about 10% to about 65%        w/w or from about 15% to about 80% w/w;    -   optionally, from about 1% w/w to about 99% w/w of a solvent        selected from the group consisting of ethanol, glycerin,        propylene glycol, polyethylene glycol 400 and a combination        thereof; and    -   optionally, from about 0.1% w/w to about 60% w/w of at least one        acid, wherein the formulation has a pH from about 2 to about        7.0.

In one aspect, the present invention is directed to epinephrine sprayformulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof, preferably the salt is selected from the group        consisting of citrate, hydrochloride, halide, sulfate,        phosphate, acetate, maleate, succinate, ascorbate, carbonate,        mesylate and lactate;    -   from about 1% w/w to about 99% w/w of a solvent selected from        the group consisting of water, ethanol, glycerin, propylene        glycol, polyethylene glycol 400 and a combination thereof,        preferably the solvent is a combination of water, ethanol and        propylene glycol or water;    -   from about 0.1% w/w to about 60% w/w of at least one acid,        preferably the at least one acid is diluted hydrochloric acid,        wherein the formulation has a pH from about 2 to about 5.5.

In another aspect, the present invention is directed to epinephrinespray formulations, wherein the formulation is free of a propellant.

In another aspect, the present invention is directed to epinephrinespray formulations, wherein the formulation does not contain sorbitol.

In another aspect, the solvent of the present invention comprises fromabout 1% w/w to about 30% w/w glycerin.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a permeation enhancer comprising caprylicacid, preferably the caprylic acid is at a concentration from about 0.1%w/w to about 10% w/w, more preferably from about 0.1% w/w to about 5%w/w.

In another aspect, the permeation enhancer of the present inventionfurther comprises a second compound selected from the group consistingof menthol, limonene, carvone, methyl chitosan, polysorbates, sodiumlauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonicacid, capric acid, undecylenic acid, lauric acid, myristic acid,palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonicacid, benzethonium chloride, benzethonium bromide, benzalkonium chloride(BKC), cetylpyridium chloride, edetate disodium dihydrate (EDTA), sodiumdesoxycholate, sodium deoxyglycolate, sodium glycocholate, sodiumcaprate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate,dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glycerylmonostearate, citric acid, peppermint oil and a combination thereof,preferably menthol, preferably the menthol is at a concentration fromabout 0.1% to about 5% w/w, more preferably from about 0.1% to about 1%w/w.

In another aspect, the epinephrine spray formulations of the presentinvention contain no permeation enhancer.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise an isotonicity agent comprising sodiumchloride.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a stabilizer selected from the groupconsisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate,sodium bisulfite, sodium metabisulfite, ascorbyl palmitate,thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride,benzalkonium chloride (“BKC”), citric acid, ethylenediaminetetraaceticacid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boricacid, histidine and combinations thereof, preferably the stabilizercomprises EDTA at a concentration from about 0.005% w/w to about 0.5%w/w, preferably the stabilizer comprises sodium bisulfite, sodiummetabisulfite or a combination thereof at a concentration from about0.005% w/w to about 5% w/w and preferably the stabilizer comprises BKCat a concentration from about 0.005% to about 0.5% w/w.

In another aspect, the epinephrine spray formulations of the presentinvention further comprise a preservative selected from the groupconsisting of butyl paraben, methyl paraben, ethyl paraben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride (BKC),benzoic acid and combinations thereof, preferably BKC at a concentrationfrom about 0.005% w/w to about 0.5% w/w.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% to about 15% w/w epinephrine, or a salt thereof;    -   from about 1% to about 65% w/w hydrochloric acid with a        normality from about 0.1 to 12N;    -   from about 2% to about 60% w/w ethanol;    -   from about 2% to about 98% w/w water;    -   from about 1% to about 20% w/w propylene glycol;    -   from about 0.001% to about 1% w/w sodium bisulfite;    -   from about 0.001% to about 1% w/w sodium metabisulfite;    -   from about 0.005% to about 1% w/w EDTA;    -   optionally, a permeation enhancer selected from the group        consisting of from about 0.5% to about 15% w/w caprylic acid,        from about 0.1% to about 10% w/w menthol and a combination        thereof; and    -   optionally, benzalkonium chloride at a concentration from about        0.001% to about 0.1% w/w, wherein the formulation optionally has        a pH from about 3 to about 7.0.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% to about 15% w/w epinephrine, or a salt thereof;    -   from about 1% to about 65% w/w hydrochloric acid with a        normality from about 0.1 to 12N;    -   from about 2% to about 98% w/w water;    -   from about 0.001% to about 7.5% w/w sodium bisulfite;    -   from about 0.001% to about 7.5% w/w sodium metabisulfite;    -   from about 0.005% to about 1% w/w EDTA;    -   from about 0.1% to about 1% sodium chloride;    -   optionally, benzalkonium chloride at a concentration from about        0.001% to about 0.1% w/w, wherein the formulation optionally has        a pH from about 3 to about 5.5.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% to about 15% w/w epinephrine, or a salt thereof;    -   from about 1% to about 65% w/w hydrochloric acid with a        normality from about 0.1 to 12N;    -   from about 2% to about 98% w/w water, preferably from about 10%        to about 65% w/w;    -   from about 0.005% to about 1% w/w sodium bisulfite;    -   from about 0.005% to about 1% w/w EDTA;    -   from about 0.005% to about 0.5% w/w BKC;    -   optionally, from about 2% to about 60% w/w ethanol;    -   optionally, from about 1% to about 20% w/w propylene glycol;    -   optionally, from about 0.05% to about 5% w/w sodium chloride;    -   optionally, benzalkonium chloride at a concentration from about        0.001% to about 0.1% w/w,        wherein the formulation optionally has a pH from about 3 to        about 7.0.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 7 milligrams of epinephrine        or a salt thereof in the formulation provides a pharmacokinetic        parameter selected from the group consisting of a C_(max) of at        least about 1000 picograms per milliliter, a T_(max) of 0.167        hours or less, an AUC_(last) of at least 750 h*pg/mL, an        AUC_(inf) of at least 950 h*pg/mL and a combination thereof.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 8.5 milligrams of        epinephrine or a salt thereof in the formulation provides a        pharmacokinetic parameter selected from the group consisting of        a C_(max) of at least about 1400 picograms per milliliter, a        T_(max) of 0.267 hours or less, an AUC_(last) of at least 1200        h*pg/mL, an AUC_(inf) of at least 1400 h*pg/mL and a combination        thereof.

In another aspect, the present invention is directed to a method oftreating anaphylaxis comprising administering to a subject in needthereof an epinephrine spray formulation of the present invention,preferably administration occurs via the intranasal route or sublingualroute and wherein, optionally, the subject is suffering from seasonalallergies.

In another aspect, the present invention is directed to a method oftreating anaphylaxis comprising administering to a subject in needthereof an epinephrine spray formulation of the present invention viaunit dose or a multi-dose device that delivers more than one dose of theformulation, preferably via a bi-dose device that delivers two doses ofthe formulation.

In another aspect the present invention is directed to a method oftreating anaphylaxis comprising administering via an assembled device anepinephrine formulation of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . Epinephrine plasma concentrations over first 6 hours postadministration.

FIG. 2 . Epinephrine plasma concentrations over first 30 minutes postadministration.

FIG. 3 . Semi-log plot of epinephrine plasma concentrations over first 6hours post administration.

FIG. 4 . Epinephrine plasma concentrations over first 6 hours postadministration.

FIG. 5 . Epinephrine plasma concentrations over first 30 minutes postadministration.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Applicants discovered epinephrine spray formulations that have improvedbioavailability, a more rapid onset of action, and improved storagestability.

As used herein, “epinephrine” refers to the base.

As used herein, “free of propellant” refers to a formulation that is notadministered using compressed gas.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 10% w/w” is to be understoodas “9% w/w to 11% w/w.” Therefore, amounts within 10% of the claimedvalue are encompassed by the scope of the claims.

As used herein “% w/w” and “percent w/w” refer to the percent weight ofthe total formulation.

As used herein the term “effective amount” refers to the amountnecessary to treat a patient in need thereof.

As used herein the term “treat”, “treating” or “treatment” refers toameliorating or inhibiting symptoms of type I allergies includinganaphylaxis.

As used herein the term “subject” refers, but is not limited to, aperson that is experiencing type I allergies including anaphylaxis.

As used herein the term “anaphylaxis” refers to an allergic reactioninvolving multiple organ systems in a subject upon contact with anallergen rather or not that allergen is identifiable.

As used herein the term “allergen” refers to any chemical capable ofcausing an immune system response in a subject including, but notlimited to, chemicals found in drugs, food, plants, insect bites, andinsect stings.

As used herein the term “seasonal allergies” refers to an allergicrhinitis. Seasonal allergies symptoms include, but are not limited to,itchy, watery eyes, sneezing, runny or stuffy nose, swollen nasalturbinates, itchy sinuses, throat or ear canals, ear congestion andpostnasal drainage.

As used herein “nasal congestion” refers to a symptom of swollen nasalturbinates.

As used herein the term “pharmaceutically acceptable” refers toingredients that are not biologically or otherwise undesirable foradministration to a living subject.

“Sublingual” refers to administration of a substance via the mouth insuch a way that the substance is rapidly absorbed via the blood vesselsunder the tongue.

“Intranasal” refers to administration of the composition to any portionof the nasal epithelium.

In one embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof.

Preferred epinephrine salts include citrate, hydrochloride, halide,sulfate, bitartrate, tartrate, phosphate, acetate, malate, maleate,succinate, ascorbate, carbonate, mesylate and lactate. One of skill inthe art could use other pharmaceutically acceptable epinephrine salts inthe formulations of the present invention. In a preferred embodiment,the formulations contain epinephrine or the pharmaceutically acceptablesalt equivalent to from about 0.1% to about 15% w/w epinephrine. In amore preferred embodiment, the formulation contains epinephrine or thepharmaceutically acceptable salt equivalent to from about 0.1% to about10% w/w of epinephrine. Other most preferred embodiments includeformulations which contain epinephrine or the pharmaceuticallyacceptable salt equivalent to from about 0.1% w/w to about 10% w/w. In amost preferred embodiment, the epinephrine concentration between 3% and10% w/w.

In another embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof, whereinthe formulation is free of a propellant.

In another embodiment, the present invention is directed to epinephrinespray formulations comprising epinephrine, or a salt thereof, and one ormore excipients selected from acids, solvents, stabilizers, permeationenhancers, viscosity modifiers, sweeteners, sweetness enhancers, pHmodifiers, isotonicity agents and flavoring agents.

In a preferred embodiment, the formulations of the present inventioncontain from about 1% to about 65% w/w of an acid, more preferably fromabout 1% to about 45% w/w. Acids suitable for use in the presentinvention include, but are not limited to, hydrochloric acid, malicacid, tartaric acid, citric acid, succinic acid and combinationsthereof. In a preferred embodiment, the acid is hydrochloric acid ormalic acid, even more preferably from about 0.1N to about 12Nhydrochloric acid, even more preferably from about 0.5 to about 6 Nhydrochloric acid, even more preferably from about 0.5 N to about 3 Nhydrochloric acid and most preferably 0.5 N or 3 N hydrochloric acid.

In a preferred embodiment, the formulations of the present inventioncontain from about 1% to 99% w/w of a solvent preferably from about 30%to about 99% w/w of the solvent.

Solvents suitable for use in the present invention include, but are notlimited to, water, ethanol, glycerin, propylene glycol, polyethyleneglycol 400 and combinations thereof, more preferably water.

In a preferred embodiment, the formulations of the present inventioncontain from about to about 10% w/w of a stabilizer, preferably fromabout 0.005% to about 7.5% w/w, and even more preferably from about0.01% to about 5% w/w. Stabilizers suitable for use in the presentinvention include, but are not limited to, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodiumascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite,ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteinehydrochloride, citric acid, ethylenediaminetetraacetic acid (“EDTA”),sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid,histidine and combinations thereof. In a preferred embodiment, thestabilizer is selected from sodium metabisulfite, sodium bisulfite,disodium EDTA, 8-hydroxyquinoline and combinations thereof. In an evenmore preferred embodiment the stabilizer is a combination of sodiumbisulfite, sodium metabisulfite, 8-Hydroxyquinoline and EDTA. In afurther preferred embodiment, the formulations of the present inventioncontain from about 0.005% to 0.5% w/w EDTA as the stabilizer. In a morepreferred embodiment, the formulations of the present invention containfrom about 0.01% to 0.1% EDTA as the stabilizer. In a most preferredembodiment, the formulations of the present invention contain about0.05% EDTA as the stabilizer. In a further preferred embodiment, theformulations of the present invention contain sodium bisulfite andsodium metabisulfite as the anti-oxidants at a concentration from aboutfrom about 0.005% to 5% w/w. In a more preferred embodiment, theformulations of the present invention contain sodium bisulfite or sodiummetabisulfite or a combination thereof as the anti-oxidants at aconcentration from about from about 0.05% to 1% w/w. In a more preferredembodiment, the formulations of the present invention contain sodiumbisulfite or sodium metabisulfite combination thereof as theanti-oxidants at a concentration from about from about 0.05% to about 1%w/w, more preferably from about 0.1% to about 0.75% w/w. In a mostpreferred embodiment, the formulations of the present invention containsodium bisulfite as the anti-oxidant at a concentration at about 0.15%or 0.3% or 0.5% or 0.75% w/w.

In some embodiments, the formulations of the present invention containfrom about w/w to about 15% w/w of a permeation enhancer, preferablyfrom about 0.03% w/w to about 12% w/w, and even more preferably fromabout 0.05% to 10% w/w.

Permeation enhancers suitable for use in the present invention include,but are not limited to, caprylic acid, oleic acid, polysorbate 80,menthol, EDTA, disodium edetate, cetylpyridinium chloride, sodium laurylsulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate,glyceryl oleate, L-lysine and combinations thereof. Preferred permeationenhancers are caprylic acid, menthol or a combination thereof.

Viscosity modifiers suitable for the present invention include, but arenot limited to, polyvinylpyrrolidone, carboxymethyl cellulose,hydroxypropylmethyl cellulose (“HPMC”), methyl cellulose, hydroxyethylcellulose, glycerin, polyvinyl alcohol and combinations thereof. In apreferred embodiment, the viscosity modifier is HPMC.

Sweeteners suitable for the present invention include, but are notlimited to, sucralose, sucrose, aspartame, saccharin, dextrose,mannitol, glycerin, xylitol and combinations thereof. In a preferredembodiment, the sweetener is sucralose.

In some embodiments, the formulations of the present invention containfrom about 0.001% to about 1% of a sweetness enhancer. Sweetnessenhancers suitable for the present invention include, but are notlimited to, the ammonium salt forms of crude and refined GlycyrrhizicAcid. Magnasweet® products (available from Mafco Worldwide Corporation,Magnasweet is a registered trademark of Mafco Worldwide Corporation) usethe ammonium salt forms of crude and refined Glycyrrhizic Acid.Glycyrrhizic Acid is also available as a pure derivative in the sodiumand potassium salt forms.

In a preferred embodiment, the formulations of the present invention areat a pH from about 2.0 to about 7.0. In a more preferred embodiment theformulations of the present invention are at a pH from about 3.0 toabout 5.0. In a further preferred embodiment, the formulations of thepresent invention are at a pH from about 4.0 to about 5.0. In a mostpreferred embodiment the formulations of the present invention are at apH of 4.5. pH modifiers suitable for the present invention include, butare not limited to, hydrochloric acid, citric acid, fumaric acid, lacticacid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodiumcarbonate, ammonium carbonate and combinations thereof.

Preservatives suitable for the present invention include, but are notlimited to, butyl paraben, methyl paraben, ethyl paraben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoicacid and combinations thereof. In a preferred embodiment, thepreservative is benzalkonium chloride. In a more preferred embodimentthe benzalkonium chloride is at a concentration from about 0.01% toabout 0.02% w/w, more preferably 0.01% or 0.02% w/w.

Flavoring agents suitable for the present invention include, but are notlimited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamonoil, strawberry flavor, cherry flavor, raspberry flavor, orange oil anda combination thereof.

In preferred embodiment, the present invention is directed toepinephrine spray formulations comprising:

-   -   from about 2.8% to about 4% w/w epinephrine, or a salt thereof;    -   from about 32% to about 38% w/w hydrochloric acid with a        normality from 0.5 to 3N;    -   from about 10% to about 65% w/w ethanol;    -   from about 2% to about 38% w/w water;    -   about 5% w/w propylene glycol;    -   from about 0.1% to about 0.75% w/w sodium bisulfite;    -   about 0.05% w/w disodium EDTA;    -   optionally, a permeation enhancer selected from the group        consisting of from about 2% to about 10% w/w caprylic acid, from        about 0.5% to about 1.0% w/w menthol and a combination thereof;        and    -   optionally, benzalkonium chloride at a concentration from about        0.01% to about 0.02% w/w, wherein the formulation optionally has        a pH of about 4.5.

In another preferred embodiment, the present invention is directed toepinephrine spray formulations comprising:

-   -   about 3.24% w/w epinephrine, or a salt thereof;    -   about 36.2% w/w hydrochloric acid with a normality of 0.5;    -   about 40% w/w ethanol;    -   about 14.84% w/w water;    -   about 5% w/w propylene glycol;    -   about 0.01% w/w benzalkonium chloride; and    -   from about 0.15% to about 0.3% w/w sodium bisulfite,    -   wherein the formulation has a pH at about 4.5.

In another preferred embodiment, the present invention is directed tointranasal epinephrine spray formulations comprising:

-   -   about 3.117% w/w epinephrine, or a salt thereof;    -   about 34.8% w/w hydrochloric acid with a normality of 0.5;    -   about 20% w/w ethanol;    -   about 36.87% w/w water;    -   about 5% w/w propylene glycol;    -   about 0.01% w/w benzalkonium chloride;    -   from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium        bisulfite,    -   wherein the formulation has a pH at about 4.5.

In another preferred embodiment, the present invention is directed tointranasal epinephrine spray formulations comprising:

-   -   about 3.04% w/w epinephrine, or a salt thereof;    -   about 33.8% w/w hydrochloric acid with a normality of 0.5;    -   about 62.35% w/w water;    -   about 0.01% w/w benzalkonium chloride;    -   from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium        bisulfite,    -   wherein the formulation has a pH at about 4.5.

An epinephrine spray formulation comprising:

-   -   about 2.96% w/w epinephrine base;    -   about 32.93% w/w hydrochloric acid with a normality of about        0.5N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 0.6% w/w sodium chloride; and    -   about 63.30% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 3.18% w/w epinephrine base;    -   about 35.47% w/w hydrochloric acid with a normality of about        0.5N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 5% w/w propylene glycol;    -   about 40.0% w/w ethanol; and    -   about 16.14% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 5.923% w/w epinephrine base;    -   about 16.46% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 0.6% w/w sodium chloride; and    -   about 76.81% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 5.923% w/w epinephrine base;    -   about 16.46% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.30% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 0.6% w/w sodium chloride; and    -   about 76.66% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 6.356% w/w epinephrine base;    -   about 17.74% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 40.0% w/w ethanol;    -   about 5% w/w propylene glycol    -   about 30.70% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 6.356% w/w epinephrine base;    -   about 17.74% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.30% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 40.0% w/w ethanol;    -   about 5% w/w propylene glycol    -   about 30.55% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 8.885% w/w epinephrine base;    -   about 24.70% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 0.6% w/w sodium chloride; and    -   about 65.61% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 8.885% w/w epinephrine base;    -   about 24.70% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.45% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 0.6% w/w sodium chloride; and    -   about 65.31% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 9.534% w/w epinephrine base;    -   about 26.60% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 40.0% w/w ethanol;    -   about 5% w/w propylene glycol    -   about 18.65% w/w water, wherein the formulation has a pH at        about 4.5.

An epinephrine spray formulation comprising:

-   -   about 9.534% w/w epinephrine base;    -   about 26.60% w/w hydrochloric acid with a normality of about 2N;    -   about 0.05% w/w edetate disodium dihydrate;    -   about 0.15% w/w sodium bisulfite;    -   about 0.01% w/w benzalkonium chloride;    -   about 40.0% w/w ethanol;    -   about 5% w/w propylene glycol    -   about 18.35% w/w water, wherein the formulation has a pH at        about 4.5.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C1 of Table 62 belowproduced an epinephrine plasma concentration more than 100 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human not exposed to anallergen of 6 milligrams of epinephrine in the formulation #C1 of Table62 below produced an epinephrine plasma concentration more than 100picograms per milliliter at about 3-minutes post administration.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C2 of Table 62 belowproduced an epinephrine plasma concentration more than 100 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human exposed to an allergenof 6 milligrams of epinephrine in the formulation #C2 of Table 62 belowproduced an epinephrine plasma concentration more than 290 picograms permilliliter at about 1-minute post administration.

In another embodiment, administration to a human not exposed to anallergen of 6 milligrams of epinephrine in the formulation #C2 of Table62 below produced an epinephrine plasma concentration more than 100picograms per milliliter at about 3-minutes post administration.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 7 milligrams of epinephrine        or a salt thereof in the formulation provides:    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (arithmetic mean) of at least about 1000 picograms        per milliliter, a T_(max) (arithmetic mean) of 0.167 hours or        less, an AUC_(last) (arithmetic mean) of at least 750 h*pg/mL,        an AUC_(inf) (arithmetic mean) of at least 950 h*pg/mL and a        combination thereof; or        a pharmacokinetic parameter selected from the group consisting        of a C_(max) (geometric mean) of at least about 500 picograms        per milliliter, a T_(max) of 0.167 hours or less, an AUC_(last)        (geometric mean) of at least about 500 h*pg/mL, an AUC_(inf)        (geometric mean) of at least about 800 h*pg/mL and a combination        thereof;    -   a pharmacokinetic parameter selected from the group consisting        of:    -   a C_(max) (arithmetic mean) of about 1040 picograms per        milliliter, a T_(max) (arithmetic mean) of about 0.167 hours, an        AUC_(last) (arithmetic mean) of about 785 h*pg/mL, an AUC_(inf)        (arithmetic mean) of about 960 h*pg/mL and a combination        thereof; or    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (geometric mean) of about 536 picograms per        milliliter, an AUC_(last) (geometric mean) of about 521 h*pg/mL,        an AUC_(inf) (geometric mean) of about 828 h*pg/mL and a        combination thereof; or    -   a plasma concentration of more than 70 picograms per milliliter        in 1 minute or less following administration;    -   a plasma concentration of more than 750 picograms per milliliter        in 3 minutes or less following administration;    -   provides a plasma concentration of more than 650 picograms per        milliliter in 5 minutes or less following administration;    -   provides a plasma concentration of more than 600 picograms per        milliliter in 7 minutes or less following administration; or    -   provides a plasma concentration of more than 550 picograms per        milliliter in 10 minutes or less following administration.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 8.5 milligrams of        epinephrine or a salt thereof in the formulation provides:    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (arithmetic mean) of at least about 1400 picograms        per milliliter, a T_(max) of 0.267 hours or less, an AUC_(last)        (arithmetic mean) of at least 1200 h*pg/mL, an AUC_(inf)        (arithmetic mean) of at least 1400 h*pg/mL and a combination        thereof;    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (geometric mean) of at least about 650 picograms        per milliliter, a T_(max) of 0.267 hours or less, an AUC_(last)        (geomteric mean) of at least about 800 h*pg/mL, an AUC_(inf)        (geometric mean) of at least about 10000 h*pg/mL and a        combination thereof;    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (arithmetic mean) of about 1420 picograms per        milliliter, a median T_(max) of about 0.267 hours, an AUC_(last)        (arithmetic mean) of about 1200 h*pg/mL, an AUC_(inf)        (arithmetic mean) of about 1440 h*pg/mL and a combination        thereof;    -   a pharmacokinetic parameter selected from the group consisting        of a C_(max) (geometric mean) of about 686 picograms per        milliliter, an AUC_(last) (geometric mean) of about 813 h*pg/mL,        an AUC_(inf) (geometric mean) of about 10308 h*pg/mL and a        combination thereof;    -   a plasma concentration of more than 200 picograms per milliliter        in 1 minute or less following administration;    -   a plasma concentration of more than 850 picograms per milliliter        in 3 minutes or less following administration;    -   a plasma concentration of more than 1000 picograms per        milliliter in 5 minutes or less following administration;    -   a plasma concentration of more than 975 picograms per milliliter        in 7 minutes or less following administration; or    -   a plasma concentration of more than 950 picograms per milliliter        in 10 minutes or less following administration.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 7 milligrams of epinephrine        or a salt thereof in the formulation provides:        a geometric mean plasma concentration at 1 minute        post-administration of 4.3 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 3 minutes        post-administration of 1.7 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 5 minutes        post-administration of 1.3 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 7 minutes        post-administration of 1.5 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 10 minutes        post-administration of 1.6 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 15 minutes        post-administration of 1.8 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 20 minutes        post-administration of 1.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 30 minutes        post-administration of 1.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 45 minutes        post-administration of 1.7 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation; or        a geometric mean plasma concentration at 60 minutes        post-administration of 2.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation,        wherein in the second formulation consists of 0.3 milligrams        epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams        sodium metabisulfite, hydrochloric acid to adjust pH, and water        for injection.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 8.5 milligrams of        epinephrine or a salt thereof in the formulation provides:        a geometric mean plasma concentration at 1 minute        post-administration of 5.3 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 3 minutes        post-administration of 1.9 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 5 minutes        post-administration of 2.0 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 7 minutes        post-administration of 2.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 10 minutes        post-administration of 2.8 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 15 minutes        post-administration of 2.8 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 20 minutes        post-administration of 2.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 30 minutes        post-administration of 2.0 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation;        a geometric mean plasma concentration at 45 minutes        post-administration of 2.7 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation; or        a geometric mean plasma concentration at 60 minutes        post-administration of 3.4 times compared to a geometric mean        plasma concentration following administration of 0.3 milligrams        of epinephrine in a second formulation,        wherein in the second formulation consists of 0.3 milligrams        epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams        sodium metabisulfite, hydrochloric acid to adjust pH, and water        for injection.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 7 milligrams of epinephrine        or a salt thereof in the formulation provides:        a geometric mean AUC_(0-0.017) of 4.2 times compared to a        geometric mean AUC_(0-0.017) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.05) of 2 times compared to a geometric        mean AUC_(0-0.5) following administration of 0.3 milligrams of        epinephrine in a second formulation;        a geometric mean AUC_(0-0.083) of 1.7 times compared to a        geometric mean AUC_(0-0.083) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.117) of 1.6 times compared to a        geometric mean AUC_(0-0.117) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.167) of 1.6 times compared to a        geometric mean AUC_(0-0.167) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.25) of 1.6 times compared to a        geometric mean AUC_(0-0.25) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.33) of 1.6 times compared to a        geometric mean AUC_(0-0.33) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.5) of 1.5 times compared to a        geometric mean AUC_(0-0.5) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.75) of 1.5 times compared to a        geometric mean AUC_(0-0.75) following administration of 0.3        milligrams of epinephrine in a second formulation; or        a geometric mean AUC₀₋₁ of 1.6 times compared to a geometric        mean AUC₀₋₁ following administration of 0.3 milligrams of        epinephrine in a second formulation.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 8.5 milligrams of        epinephrine or a salt thereof in the formulation provides:        a geometric mean AUC_(0-0.017) of 5 times compared to a        geometric mean AUC_(0-0.017) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.05) of 2.3 times compared to a        geometric mean AUC_(0-0.5) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.083) of 2.1 times compared to a        geometric mean AUC_(0-0.083) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.117) of 2.1 times compared to a        geometric mean AUC_(0-0.117) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.167) of 2.3 times compared to a        geometric mean AUC_(0-0.167) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.25) of 2.5 times compared to a        geometric mean AUC_(0-0.25) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.33) of 2.5 times compared to a        geometric mean AUC_(0-0.33) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.5) of 2.4 times compared to a        geometric mean AUC_(0-0.5) following administration of 0.3        milligrams of epinephrine in a second formulation;        a geometric mean AUC_(0-0.75) of 2.4 times compared to a        geometric mean AUC_(0-0.75) following administration of 0.3        milligrams of epinephrine in a second formulation; or        a geometric mean AUC₀₋₁ of 2.5 times compared to a geometric        mean AUC₀₋₁ following administration of 0.3 milligrams of        epinephrine in a second formulation.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 3% to about 6% w/w epinephrine base;    -   from about 20% to about 30% w/w hydrochloric acid with a        normality of about 1.0N;    -   from about 0.025% to about 0.075% w/w edetate disodium        dihydrate;    -   from about 0.15% to about 0.30% w/w sodium bisulfite;    -   from about 0.005% to about 0.02% w/w benzalkonium chloride;    -   from about 35% to about 45% w/w ethanol;    -   from about 2.5% to about 7.5% w/w propylene glycol; and    -   from about 20% to about 30% w/w water.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 3% to about 5% w/w epinephrine base;    -   from about 20% to about 25% w/w hydrochloric acid with a        normality of about 1.0N;    -   from about 0.025% to about 0.075% w/w edetate disodium        dihydrate;    -   from about 0.15% to about 0.25% w/w sodium bisulfite;    -   from about 0.005% to about 0.02% w/w benzalkonium chloride;    -   from about 35% to about 45% w/w ethanol;    -   from about 2.5% to about 7.5% w/w propylene glycol; and    -   from about 20% to about 40% w/w water.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   from about 0.1% w/w to about 15% w/w epinephrine or a salt        thereof;    -   from about 2% to about 10% w/w propylene glycol;    -   from about 20% to about 50% w/w ethanol; and    -   from about 1% to about 80% w/w water,        wherein administration to a human of 7 milligrams of epinephrine        or a salt thereof in the formulation provides:    -   a geometric mean C_(max) of about 86.2% compared to a geometric        mean C_(max) following intramuscular administration of 0.3        milligrams of epinephrine in a second formulation;    -   AUC_(last) of about 154% compared to a geometric mean AUC_(last)        following administration of 0.3 milligrams of epinephrine in a        second formulation;    -   AUC_(inf) of about 217% compared to a geometric mean AUC_(inf)        following administration of 0.3 milligrams of epinephrine in a        second formulation;    -   a geometric mean C_(max) of about 101% compared to a geometric        mean C_(max) following intramuscular administration of 0.5        milligrams of epinephrine in a third formulation;    -   AUC_(last) of about 94.5% compared to a geometric mean        AUC_(last) following administration of 0.5 milligrams of        epinephrine in a third formulation; or    -   AUC_(inf) of about 120% compared to a geometric mean AUC_(inf)        following administration of milligrams of epinephrine in a third        formulation,        wherein the second formulation consists of 0.3 milligrams        epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams        sodium metabisulfite, hydrochloric acid to adjust pH, and water        for injection and wherein the third formulation consists of 1.0        milligrams epinephrine, 6.15 milligrams sodium chloride, 0.457        milligrams sodium metabisulfite, 0.920 milligrams sodium        hydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams        disodium edetate dihydrate, hydrochloric acid to adjust pH,        milligrams chlorobutanol and water for injection.

In another aspect, the present invention is directed to epinephrinespray formulations comprising:

-   -   a geometric mean C_(max) of about 111% compared to a geometric        mean C_(max) following administration of 0.3 milligrams of        epinephrine in a second formulation;    -   AUC_(last) of about 241% compared to a geometric mean AUC_(last)        following administration of 0.3 milligrams of epinephrine in a        second formulation;    -   AUC_(inf) of about 282% compared to a geometric mean AUC_(inf)        following administration of 0.3 milligrams of epinephrine in a        second formulation;    -   a geometric mean C_(max) of about 130% compared to a geometric        mean C_(max) following intramuscular administration of 0.5        milligrams of epinephrine in a third formulation;    -   AUC_(last) of about 147% compared to a geometric mean AUC_(last)        following administration of 0.5 milligrams of epinephrine in a        third formulation; or    -   AUC_(inf) of about 155% compared to a geometric mean AUC_(inf)        following administration of milligrams of epinephrine in a third        formulation,        wherein the second formulation consists of 0.3 milligrams        epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams        sodium metabisulfite, hydrochloric acid to adjust pH, and water        for injection and wherein the third formulation consists of 1.0        milligrams epinephrine, 6.15 milligrams sodium chloride, 0.457        milligrams sodium metabisulfite, 0.920 milligrams sodium        hydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams        disodium edetate dihydrate, hydrochloric acid to adjust pH,        milligrams chlorobutanol and water for injection.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (10) is from about 15 to about 18 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (50) is from about 30 to about 34 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 3 cm wherein themean DV (90) is from about 120 to about 230 microns duringadministration.

In another embodiment, the formulations of the present invention arecapable of producing a spray span ((Dv90-Dv10)/Dv50) at 3 cm of fromabout 3 to about 7.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (10) is from about 22 to about 25 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (50) is from about 36 to about 41 microns during administration.

In another embodiment, the formulations of the present invention arecapable of producing a droplet size distribution at 6 cm wherein themean DV (90) is from about 59 to about 231 microns duringadministration.

In another embodiment, the formulations of the present invention arecapable of producing a spray span ((Dv90-Dv10)/Dv50) at 6 cm of fromabout 1 to about 6.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the Dmin is fromabout 18 to about 23 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the Dmax is fromabout 29 to about 33 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 3 cm wherein the ovality ratiois from about 1.4 to about 1.7 during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the Dmin is fromabout 26 to about 33 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the Dmax is fromabout 47 to about 52 millimeters during administration.

In another embodiment, the formulations of the present invention arecapable of producing a spray pattern at 6 cm wherein the ovality ratiois from about 1.6 to about 1.9 during administration.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the angle is fromabout 49° to about 64°.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the width is fromabout 27 to about 38 millimeters.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the angle is fromabout 37° to about 44°.

In another embodiment, the formulations of the present invention arecapable of producing a plume geometry at 3 cm wherein the width is fromabout 37 to about 44 millimeters.

In one embodiment, the present invention is directed to a method oftreating anaphylaxis comprising administering via an assembled device anepinephrine formulation comprising from about 0.1% w/w to about 15% w/wepinephrine or a salt thereof and from about 1% to about 80% w/w water,wherein the formulation has a pH from about 2 to about 7.0.

In a preferred embodiment, the assembled device comprises a reservoir, aplunger, a cannula, a spray pin, a reservoir holder and an actuator or areservoir, a piston and a swirl chamber.

In another preferred embodiment, the assembled device delivers one ormore doses of the epinephrine formulation.

In another preferred embodiment, the assembled device is a unit-dosedevice that delivers one dose of the epinephrine formulation upon asingle actuation and comprises a single reservoir containing not morethan 250 μL of the epinephrine formulation, preferably about 237 μL ornot more than 140 μL, preferably about 127 μL.

In another preferred embodiment, the assembled device is a unit-dosedevice that delivers about 200 μL or about 100 μL of the pharmaceuticalformulation upon a single actuation.

In another preferred embodiment, the assembled device is a bi-dosedevice that delivers two doses of the epinephrine formulation upon twoactuations and delivers about 100 μL of the epinephrine formulation peractuation.

In another preferred embodiment, the assembled device is a multi-dosedevice that delivers multiple doses of the epinephrine formulation uponmultiple actuations and delivers about 100 μL of the pharmaceuticalsolution per actuation.

The disclosed embodiments are simply exemplary embodiments of theinventive concepts disclosed herein and should not be considered aslimiting, unless the claims expressly state otherwise.

The following examples are intended to illustrate the present inventionand to teach one of ordinary skill in the art how to use theformulations of the invention. They are not intended to be limiting inany way.

EXAMPLES Example 1

An epinephrine spray was prepared as follows using the components andamounts listed in Table 1 below. All of the solvents were purged withnitrogen prior to use. Excipients including 0.5 N hydrochloric acid(“HCl”), malic acid, ethanol and propylene glycol, EDTA, sodiumchloride, sodium bisulfite, sodium metabisulfite, and 8-hydroxyquinolinewere dissolved in water while stirring at room temperature. Epinephrinebase was then added to the excipient solution. Finally, sodium hydroxide(“NaOH”)/hydrochloric acid (HCl)) was used to adjust final pH.

TABLE 1 Epinephrine Formulations % w/w #1 #2 #3 #4 #5 #6 #7 #8 #9 #10#11 Epinephrine base 1.0 1.0 1.0 1.0 1.0 7.5 1 3.0 3.0 3.0 3.0 HCl(0.5N) 10.66 10.66 10.66 10.66 10.66 — 11.35 — 32.6 32.6  32.6 EDTA 0.050.05 0.05 0.05 0.05 — — — 0.05  0.05 0.05 Sodium metabisulfite 0.010.015 0.02 0.025 0.025 0.25 0.025 0.04 — — — sodium bisulfite 0.01 0.0150.02 0.025 0.025 — 0.025 0.05 0.2 0.2 Propylene Glycol — — — — — — — — —— 5 Menthol — — — — — — — — — — 5 Chlorobutanol — — — — — — — — — 0.5 —Sucralose — — — — — — — — — 0.5 0.5 8-Hydroxyquinoline — — — — 0.02 — —— — — — Ethanol — — — — — 15 — — — 50 Malic Acid — — — — — 2.0 — 1.65 —— — Water 88.27 88.26 88.25 88.24 88.22 79.75 87.6 95.31 64.3 63.15 4.15100 100 100 100 100 100 100 100 100 100    100 pH adjusted with NaOH pH4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH 4.5 pH4.5

Example 2

The formulations listed in Table 1 were subjected to stability at 40°C.±2° C./75%±5% relative humidity and 25° C.±2° C./60%±5% relativehumidity. The stability of the formulations was analyzed at specifiedtime points by evaluating their potency (assay value) and impuritylevels. Assay and impurities were detected using high-performance liquidchromatography with an ultraviolet detector. The assay was performed at280 nm and indicated as a % of initial concentration. For allimpurities, analysis was performed at 210 nm and 280 nm and expressed asa % area. Amounts of particular impurities are listed in Tables 2 to 20as a percentage of area of each formulation along with amount of totalimpurities. Relative retention time (“RRT”) is given for each impurity.“ND” indicates that the impurity was not detected. “BQL” indicatespurity is below quantification limit.

TABLE 2 Stability Data for Epinephrine Spray Formulation #1 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #1 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00 97.94 95.80 % Racemization   0.60  0.93  1.54 pH   4.50 3.52  3.29 % Impurity F 0.19   0.13  1.07  1.51 % Synephrine 1.26  NDND ND % Epinephrone 1.36  ND ND ND % Methoxy 1.88   0.07  0.07  0.07 %Unknown Impurity 0.21  ND  0.10  0.15 0.23  ND ND  0.02 3.11  ND  BQL 0.03 3.26  ND  BQL  0.02 % Total Impurities   0.20  1.24  1.80

TABLE 3 Stability Data for Epinephrine Spray Formulation #2 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #2 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00 96.02 97.32 % Racemization   0.60  0.91  1.77 pH   4.50 3.39  3.14 % Impurity F 0.19   0.14  1.27  1.91 % Synephrine 1.26  NDND ND % Epinephrone 1.38  ND ND  BQL % Methoxy 1.88   0.07  0.07  0.07 %Unknown Impurity 0.21  ND  0.10  0.11 0.23  ND ND  BQL 3.26  ND ND ND %Total Impurities   0.21  1.44  2.09

TABLE 4 Stability Data for Epinephrine Spray Formulation #3 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #3 RRT 0Week 2 Weeks 4 Weeks 8 Weeks 3 Months Appearance Clear Clear Clear ClearClear Assay (% of initial conc.) 100.00  98.22  96.87  94.56  93.27  %Racemization 0.60 1.01 1.48 3.67 4.23 pH 4.50 3.37 3.14 3.01 — %Impurity F 0.19 0.13 1.27 2.19 3.05 3.18 % Synephrine 1.26 ND ND ND NDND % Epinephrone 1.36 ND ND BQL BQL BQL % Methoxy 1.88 0.07 0.07 0.070.07 0.07 % Unknown Impurity 0.21 ND 0.08 0.07 0.08 0.24 3.11 ND ND BQLBQL BQL 3.26 ND ND BQL BQL BQL % Total Impurities 0.20 1.42 2.33 3.203.49

TABLE 5 Stability Data for Epinephrine Spray Formulation #4 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation 0 1 2 4 6 83 4 #4 RRT Week Week Weeks Weeks Weeks Weeks Months Months AppearanceClear Clear Clear Clear Clear Clear Clear Clear Assay (% of 100.0 100.798.54 98.35 96.02 94.44 92.60 89.34 initial conc.) % 0.60 0.68 — — 3.413.46 5.75 9.20 Racemization % Impurity F 0.19 0.15 0.78 1.29 2.33 3.163.83 4.36 4.65 % Synephrine 1.26 ND ND ND ND ND ND ND ND % 1.36 ND ND NDBQL BQL BQL BQL BQL Epinephrone % Methoxy 1.88 0.08 0.08 0.08 0.08 0.080.08 0.08 0.09 % Unknown 0.21 ND ND 0.05 0.08 0.07 0.09 0.22 0.23Impurity 3.11 ND ND ND BQL BQL BQL BQL 0.05 3.26 ND ND ND BQL BQL BQLBQL BQL % Total 0.23 0.86 1.42 2.49 3.31 4.00 4.66 5.02 Impurities

TABLE 6 Stability Data for Epinephrine Spray Formulation #5 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. 0 2 4 8 3 Formulation#5 RRT Week Weeks Weeks Weeks Months Appearance Clear Clear Clear ClearClear Assay 100.00  98.36  96.88  95.35  93.34  (% of initial conc.) %Racemization 0.60 0.85 1.08 2.63 4.23 pH 4.50 3.64 3.37 3.20 — %Impurity F 0.19 0.15 1.48 2.50 3.50 3.75 % Synephrine 1.26 ND ND ND NDND % Epinephrone 1.36 ND ND BQL BQL BQL % Methoxy 1.88 0.07 0.07 0.070.07 0.07 % Unknown 0.21 ND 0.10 0.11 0.15 0.35 Impurity 0.88 ND ND NDND BQL 3.11 ND ND BQL BQL BQL 3.26 ND ND BQL BQL BQL % Total Impurities0.22 1.65 2.68 3.72 4.17

TABLE 7 Stability Data for Epinephrine Spray Formulation #6 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #6 RRT 0Week 2 Weeks 1 Month Appearance Clear Clear Clear Assay (% of initialconc.) 100.00 97.75 95.95 % Impurity F 0.19   0.15  2.38  4.04 %Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND  BQL  BQL % Methoxy 1.88 BQL  BQL  BQL % Unknown Impurity 0.21 ND  0.05  0.08 % Total Impurities  0.15  2.43  4.08

TABLE 8 Stability Data for Epinephrine Spray Formulation #7 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #7 RRT 0Week 2 Weeks 4 Weeks Appearance Clear Clear Clear % Impurity F 0.19 0.321.85 2.75 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND ND ND %Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 0.17 0.36 0.44 %Total Impurities 0.56 2.28 3.26

TABLE 9 Stability Data for Epinephrine Spray Formulation #8 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #8 RRT 0Week 2 Weeks Appearance Clear Light Brown Assay (% of initial conc.)100.00 95.55 % Racemization   0.63  0.62 % Impurity F 0.19   0.22  1.56% Synephrine 1.26  ND ND % Epinephrone 1.36  ND ND % Methoxy 1.88   0.07 0.07 0.21  ND  0.12 0.26  ND  BQL % Unknown Impurity 0.88  ND  BQL 3.11 ND  BQL 3.26  ND  BQL % Total Impurities   0.29  1.75

TABLE 10 Stability Data for Epinephrine Spray Formulation #9 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #9 RRT 0Week 1 Week 4 Weeks Appearance Clear Clear Clear Assay (% of initialconc.) 100.00 100.76 99.73 % Racemization   0.60   0.68 — % Impurity F0.19   0.15   0.84 1.86 % Synephrine 1.26  ND  ND ND % Epinephrone 1.36 ND  ND ND % Methoxy 1.88   0.07   0.07 0.07 0.21  ND  ND 0.06 % UnknownImpurity 3.11  ND  BQL 0.09 3.26  ND  BQL 0.08 % Total Impurities   0.22  0.91 2.16

TABLE 11 Stability Data for Epinephrine Spray Formulation #10 stored at40°C. ± 2°C./75% ± 5% Relative Humidity 40°C. Formulation #10 RRT 0 Week1 Week Appearance Clear Clear Assay (% of initial conc.) 100.00 100.76 %Racemization 0.60 0.68 % Impurity F 0.19 0.12 2.89 % Synephrine 1.26 NDND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07 % Unknown Impurity0.21 ND BQL 3.11 ND BQL 3.26 ND BQL % Total Impurities 0.19 2.96

TABLE 12 Stability Data for Epinephrine Spray Formulation #11 stored at40° C. ± 2° C./75% ± 5% Relative Humidity 40° C. Formulation #11 RRT 0Week 1 Week Appearance Clear Clear Assay (% of initial conc.) 100.00100.76 % Racemization  0.60  0.68 % Impurity F 0.19  0.12  0.90 %Synephrine 1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88  0.07 0.07 % Unknown Impurity 0.21 ND BQL 3.11 ND BQL 3.26 ND BQL % TotalImpurities  0.19  0.97

TABLE 13 Stability Data for Epinephrine Spray Formulation #1 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #1 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial100.00 97.91 97.32 conc.) % Racemization  0.60  0.76  0.93 % Impurity F0.19  0.13  0.53  1.04 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 NDND ND % Methoxy 1.88  0.07  0.07  0.07 % Unknown Impurity 0.21 ND  0.05 0.19 3.11 ND ND BQL 3.26 ND ND BQL % Total Impurities  0.20  0.65  1.30

TABLE 14 Stability Data for Epinephrine Spray Formulation #2 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #2 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial100.00 97.56 96.88 conc.) % Racemization  0.60  0.78  1.01 % Impurity F0.19  0.14  0.55  1.25 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 NDND ND % Methoxy 1.88  0.07  0.07  0.07 % Unknown Impurity 0.21 ND  0.08 0.18 3.11 ND ND BQL 3.26 ND ND BQL % Total Impurities  0.21  0.70  1.50

TABLE 15 Stability Data for Epinephrine Spray Formulation #3 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #3 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial100.00 99.32 98.16 conc.) % Racemization  0.60  0.75  0.84 % Impurity F0.19  0.13  0.52  1.29 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 NDND ND % Methoxy 1.88  0.07  0.07  0.07 % Unknown Impurity 0.21 ND BQL 0.09 3.11 ND ND BQL 3.26 ND ND BQL % Total Impurities  0.20  0.59  1.45

TABLE 16 Stability Data for Epinephrine Spray Formulation #4 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. 0 3 4 8 3 6 Formulation#4 RRT Week Weeks Weeks Weeks Months Months Appearance Clear Clear ClearClear Clear Clear Assay (% of initial 100.00  100.76  99.79  99.31 99.09  98.69  conc.) % Racemization 0.60 0.68 — 0.91 0.97 — % Impurity F0.19 0.15 0.41 0.50 1.01 1.46 2.39 % Synephrine 1.26 ND ND ND ND ND ND %Epinephrone 1.36 ND ND ND ND BQL BQL % Methoxy 1.88 0.08 0.08 0.08 0.080.08 0.08 % Unknown Impurity 0.21 ND 0.05 0.06 0.06 0.11 0.10 3.02 ND NDND ND ND 0.12 3.11 ND ND ND ND ND 0.12 3.26 ND ND ND ND ND 0.10 % TotalImpurities 0.23 0.54 0.64 1.15 1.65 2.91

TABLE 17 Stability Data for Epinephrine Spray Formulation #5 stored at25° C. ± 2° C./ 60% ± 5% Relative Humidity 25° C. Formulation #5 RRT 0Week 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial100.00 98.40 97.29 conc.) % Racemization  0.60  0.77  0.84 % Impurity F0.19  0.15  0.67  1.41 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 NDND ND % Methoxy 1.88  0.07  0.07  0.07 % Unknown Impurity 0.21 ND  0.05 0.18 3.11 ND ND BQL 3.26 ND ND BQL % Total Impurities  0.22  0.79  1.66

TABLE 18 Stability Data for Epinephrine Spray Formulation #6 stored at25° C. ± 2° C./ 60% ± 5% Relative Humidity 25° C. Formulation #6 RRT 0Week 2 Weeks 1 Month 6 Months Appearance Clear Clear Clear Clear Assay(% of initial 100.00 100.25 99.75 94.80 conc.) % Impurity F 0.19  0.15 0.45  0.76  2.93 % Synephrine 1.26 ND ND ND ND % Epinephrone 1.36 NDBQL BQL BQL % Methoxy 1.88 BQL BQL BQL BQL % Unknown Impurity 0.21 ND NDBQL  0.30 0.26 ND ND ND  0.13 0.88 ND ND ND  0.15 2.58 ND ND ND  0.103.11 ND ND ND  0.24 3.26 ND ND ND  0.17 % Total Impurities  0.15  0.45 0.76  4.02

TABLE 19 Stability Data for Epinephrine Spray Formulation #8 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #8 RRT 0Week 1 Month Appearance Clear Clear Assay (% of initial 100.00 99.21conc.) % Racemization 0.63 0.66 % Impurity F 0.19 0.22 0.64 % Synephrine1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07 % UnknownImpurity 0.21 ND 0.06 3.11 ND BQL 3.26 ND BQL % Total Impurities 0.290.77

TABLE 20 Stability Data for Epinephrine Spray Formulation #9 stored at25° C. ± 2° C./60% ± 5% Relative Humidity 25° C. Formulation #9 RRT 0Week 1 Month 6 Months Appearance Clear Clear Clear Assay (% of initial100.00 99.64 98.88 conc.) % Impurity F 0.19 0.15 0.52 1.71 % Synephrine1.26 ND ND ND % Epinephrone 1.36 ND ND ND % Methoxy 1.88 0.08 0.07 0.07% Unknown Impurity 0.21 ND 0.05 0.07 3.11 ND BQL 0.09 3.26 ND BQL 0.08 %Total Impurities 0.23 0.64 2.02

Formulations #1-#5 had less than 3% total impurities after 4 Weeks (1Month) at 40° C.±2° C./75%±5% Relative Humidity and less than 1% totalimpurities after 4 Weeks (1 Month) at 25° C.±2° C./60%±5% relativehumidity. Of Formulations #6-#8, only Formulation #8 was analyzed at 4Weeks or later at 40° C. where 4.68% total impurities were found.Formulation #9 exhibited total impurities of 2.17% at 4 weeks 40° C.Formulation #11 exhibited total impurities of 1% at one week 40° C. Thesuperior and surprising stability characteristics of the formulations ofthe present invention will allow the formulations to be effective whenused by patients.

When compared with formulation 4, formulation 7 showed a fastergeneration of impurities and was not stable for more than a month at 40°C. Formulation 4 was stable for 4 months when stored at 40° C. whichindicates that EDTA increases the stability of epinephrine formulations.

Example 3

Formulation #4 was further tested for stability during freeze-thawcycling. Specifically, Formulation #4 was run through 3 cycles of −20 °C. for 48 hours and then 25° C. for 48 hours, where the physicalappearance of the formulation was recorded. The formulation remainedclear and colorless throughout the entire freeze-thaw cycling indicatinga stable formulation throughout.

Example 4

In order to determine the spray profile of Formulation #4, it wassubjected to standardized droplet testing. A challenge of creating anepinephrine spray formulation is that it must be capable of producingspray droplets that are over 10 microns in diameter. Spray droplets of10 microns or smaller could be inhaled into the lungs.

Droplet analysis was conducted using standard laser analysis proceduresknown by those of skill in the art. Droplet size distribution (Dv₁₀,Dv₅₀, Dv₉₀, and Span) was tested at two distances, 3 cm and 6 cm. Dv₁₀refers to the droplet size at which 10% of the volume is smaller; Dv₅₀refers to the median droplet size; Dv90 refers to droplet size for which90% of the total volume is smaller; Span refers to distribution span(Dv90-Dv10)/Dv50. %<10 μm refers to the percentage of the total volumethat is made up of droplets less than 10 μm in diameter.

Spray pattern, specifically Dmin, Dmax, and ovality ratio were tested attwo distances, 3 cm and 6 cm. Dmin refers to the shortest diameter ofthe spray pattern in mm, Dmax refers to the widest diameter of the spraypattern in mm, and ovality ratio refers to the ratio of Dmax to Dmin.The spay pattern is measured by shining a laser sheet perpendicular tothe spray at a specific distance from the orifice. The ovality ratio isuseful as it provides information regarding the shape and density of thespray pump plume.

The results of these tests can be seen below in Tables 17 to 22.

TABLE 21 Droplet size distribution of Epinephrine Spray Formulation at 3cm Droplet Size Distribution 3 cm DV₁₀ (μm) DV₅₀ (μm) DV₉₀ (μm) % <10 μmSpan Min 15.8 30.84 124 0.05 3.145 Max 17.23 33.96 228.7 0.89 6.283 Mean16.34 32.88 177.9 0.473 4.93

TABLE 22 Droplet size distribution of Epinephrine Spray Formulation at 6cm Droplet Size Distribution 6 cm DV₁₀ (μm) DV₅₀ (μm) DV₉₀ (μm) % <10 μmSpan Min 22.72 36.07 59.52 0 1.017 Max 24.05 40.35 230.9 0 5.127 Mean23.2 38.48 121.5 0 2.49

TABLE 23 Spray pattern of Epinephrine Spray Formulation at 3 cm DminDmax Ovality Spray Pattern 3 cm (mm) (mm) ratio Min 18.9 29.8 1.415 Max22.2 32.1 1.696 Mean 20.4 31.1 1.53

TABLE 24 Spray pattern of Epinephrine Spray Formulation at 6 cm DminDmax Ovality Spray Pattern 6 cm (mm) (mm) ratio Min 26.5 47 1.68 Max32.2 54.2 1.852 Mean 29.1 51.4 1.768

TABLE 25 Plume geometry of Epinephrine Spray Formulation at 3 cm WidthPlume Geometry 3 cm Angle (°) (mm) Min 49.2 27.6 Max 63.4 37.8 Mean 55.432.2

TABLE 26 Plume geometry of Epinephrine Spray Formulation at 6 cm WidthPlume Geometry 6 cm Angle (°) (mm) Min 37.7 37.7 Max 43.5 43.5 Mean 40.740.7

Applicant found during testing that formulations of the presentinvention yielded desirable droplet sizes for spray administration. Thetesting also revealed that the formulation dose remains consistent whenadministered with a spray pump.

Example 5. Preparation of Additional Hydro-alcoholic Epinephrine SprayFormulations

Additional epinephrine spray formulations were prepared using thecomponents and amounts listed in Table 27 below. All solvents werepurged with nitrogen prior to use. Excipients including 0.5 N or 1.0 Nhydrochloric acid (“HCl”), ethanol, propylene glycol, EDTA, sodiumbisulfite and/or caprylic acid were dissolved in water while stirring atroom temperature. Epinephrine base was then added to the excipientsolution. Finally, sodium hydroxide (“NaOH”)/hydrochloric acid (“HCl”)was used to adjust final pH.

TABLE 27 Additional Hydro-alcoholic Epinephrine Spray Formulations % w/w#12 #13 #14 #15 #16 #17 #18 #19 #20 Epinephrine base 3.2 3.2 3.2 3.2 3.23.38 3.38 3.24 3.12 Hydrochloric acid (0.5N) 34.6 34.6 34.6 34.6 34.637.7 37.7 36.2 34.8 EDTA 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05Sodium bisulfite 0.1 0.15 0.20 0.25 0.30 0.15 0.15 0.15 0.15 PropyleneGlycol 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Caprylic acid — — — — — 2.010.0 — — Benzalkonium chloride — — — — — 0.02 0.02 0.01 0.01 Menthol 1.01.0 1.0 1.0 1.0 0.5 0.5 — — Sucralose 0.5 0.5 0.5 0.5 0.5 0.5 0.5 — —Ethanol 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 20.0 Water 15.55 15.5015.45 15.40 15.35 10.7 2.7 15.35 36.87 pH adjusted with 4.5 4.5 4.5 4.54.5 4.5 4.5 4.5 4.5 2 NaOH/0.5N HCl

TABLE 28 Additional Aqueous based Epinephrine Spray Formulation % w/w#21 #22 #23 #24 #25 #26 Epinephrine base 3.040 3.040 3.040 3.040 3.0403.040 Hydrochloric 33.80 33.80 33.80 33.80 33.80 33.80 acid (0.5N) EDTA0.05 0.05 0.05 0.05 0.05 0.05 Sodium bisulfite 0.150 0.250 0.5 1.00 2.005.00 Benzalkonium 0.01 0.01 0.01 0.01 0.01 0.01 chloride Sodium Chloride0.6 0.6 0.6 0.6 0.6 0.6 Water 62.35 62.25 62.00 61.5 60.5 57.5 pHadjusted 4.5 4.5 4.5 4.5 4.5 4.5 with 2 NaOH/0.5N HCl

TABLE 29 Additional Epinephrine (6 mg/spray) Formulations % w/w Function#27 #28 #29 #30 Epinephrine base Active 5.923 6.356 5.923 6.356Ingredient Benzalkonium chloride Preservative 0.010 0.010 0.010 0.010Sodium Chloride Tonicity 0.600 — 0.600 — Agent Sodium bisulfiteAnti-Oxidant 0.150 0.150 0.300 0.300 Edetate Disodium Chelating 0.0500.050 0.050 0.050 Dihydrate (EDTA) agent Hydrochloric acid pH modifier16.462 17.736 16.462 17.736 (2N) Purified Water Vehicle 76.805 30.69876.655 30.548 Dehydrated Alcohol Co-Solvent — 40.000 — 40.000 (Ethanol)Propylene Glycol Co-Solvent — 5.000 — 5.000 Solution containing pHAdjust to Adjust to Adjust to Adjust to 2.0N NaOH and adjustment pH 4.5± 0.1 pH 4.5 ± 0.1 pH 4.5 ± 0.1 pH 4.5 ± 0.1 0.5N HCl

TABLE 30 Additional Epinephrine (9 mg/spray) Formulations % w/w Function#31 #32 #33 #34 Epinephrine base Active 8.885 9.534 8.885 9.534Ingredient Benzalkonium chloride Preservative 0.010 0.010 0.010 0.010Sodium Chloride Tonicity 0.600 — 0.600 — Agent Sodium bisulfiteAnti-Oxidant 0.150 0.150 0.45 0.45 Edetate Disodium Chelating 0.0500.050 0.050 0.050 Dihydrate (EDTA) agent Hydrochloric acid pH modifier24.695 26.603 24.695 26.603 (2N) Purified Water Vehicle 65.610 18.65365.310 18.353 Dehydrated Alcohol Co-Solvent — 40.000 — 40.000 (Ethanol)Propylene Glycol Co-Solvent — 5.000 — 5.000 Solution containing pHAdjust to Adjust to Adjust to Adjust to 2.0N NaOH and adjustment pH 4.5± 0.1 pH 4.5 ± 0.1 pH 4.5 ± 0.1 pH 4.5 ± 0.1 0.5N HCl

TABLE 31 Epinephrine (3-5 mg/spray) Formulations % w/w Function #35 #36#37 #38 Epinephrine base Active 3.178 2.962 3.885 4.702 IngredientBenzalkonium chloride Preservative 0.010 0.010 0.010 0.010 SodiumChloride Tonicity — 0.6 — — Agent Sodium bisulfite Anti-Oxidant 0.1500.150 0.184 0.223 Edetate Disodium Chelating 0.050 0.050 0.050 0.050Dihydrate (EDTA) agent Hydrochloric acid pH modifier 35.471 32.93621.681 26.241 (0.5N) (0.5N) (1.0N) (1.0N) Purified Water Vehicle 16.14163.298 29.190 23.774 Dehydrated Alcohol Co-Solvent 40.000 — 40.00040.000 (Ethanol) Propylene Glycol Co-Solvent 5.000 — 5.000 5.000Solution containing pH Adjust to Adjust to 2.0N NaOH and adjustment pH4.5 ± 0.1 pH 4.5 ± 0.1 0.5N HCl

The formulations listed in Table 27 and Table 28 were filled in unitdose devices, packed into an oxygen impermeable pouches with oxygenscavengers, and then subjected to stability at 40° C.±2° C./75%±5%relative humidity and 25° C.±2° C./60%±5% relative humidity. Thestability of the formulations was analyzed at specified time points byevaluating their potency (assay value) and impurity levels. Assay andimpurities were detected using high-performance liquid chromatographywith an ultraviolet detector. The assay was performed at 280 nm andindicated as a % of initial concentration. For all impurities, analysiswas performed at 210 nm and 280 nm and expressed as a % area. Amounts ofparticular impurities are listed in Tables 32 to 55 as a percentage ofarea of each formulation along with amount of total impurities. Relativeretention time (“RRT”) is given for each impurity. “ND” indicates thatthe impurity was not detected. Any impurity which is less than 0.05% isindicated as BQL. NP refers to Not Performed.

TABLE 32 Stability Data for Epinephrine Spray Formulations # 12 to # 16stored at 25° C. ± 2° C./60% ± 5% Relative Humidity Stability @18 M 25°C./60% RH F # 12 F # 13 F # 14 F # 15 F # 16 RRT 0 Week 18 months 18Months 18 Months 18 months 18 months Appearance Clear Clear Clear ClearClear Clear % Impurity F 0.19 0.11 1.91 2.53 3.27 3.57  4.79* %Synephrine 1.26 ND ND ND ND ND ND % Epinephrone 1.36 ND BQL BQL BQL BQLBQL % Methoxy 1.90 0.07 0.08 0.08 0.07 0.07 0.08 % Unknown Impurities0.22 0.01 0.12 0.12 0.13 0.12 0.12 0.25 ND 0.09 BQL BQL ND 0.07 0.26 NDND ND ND ND ND 0.64 ND ND ND ND ND BQL 0.88 ND BQL BQL BQL BQL BQL 1.21ND 0.09 0.09 0.08 BQL 0.06 1.34 ND BQL 0.05 BQL BQL BQL 1.50 ND ND ND0.07 BQL BQL 1.51 ND 0.1  0.07 ND ND ND 2.43 ND ND ND ND 0.06 ND 2.44 NDND 0.07 0.08 ND ND 2.45 ND 0.11 ND ND ND ND 2.57 ND ND ND ND ND 0.062.71 ND ND ND ND ND ND 2.90 ND ND ND BQL ND ND 2.91 ND ND BQL ND ND ND2.93 ND 0.07 ND ND ND ND 2.96 ND ND ND ND ND ND 3.11 ND 0.05 BQL BQL BQLBQL 3.26 ND ND BQL ND ND ND Total Impurities 0.19 2.62 3.01 3.70 3.825.18

TABLE 33 Stability Data for Epinephrine Spray Formulation # 17 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT 1 Month 2 Month AppearanceClear Clear % Impurity F 0.19 0.50 0.72 % Epinephrone 1.36 ND ND %Methoxy 1.90 0.07 0.07 % Unknown 1.08 0.14 0.08 Impurities % TotalImpurities 0.71 0.87

TABLE 34 Stability Data for Epinephrine Spray Formulation # 18 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT 1 Month 2 MonthsAppearance Clear Clear % Impurity F 0.19 0.57 0.75 % Epinephrone 1.36 NDND % Methoxy 1.90 0.07 0.07 1.08 0.08 0.14 1.12 BQL 0.07 % TotalImpurities 0.72 1.03

TABLE 36 Stability Data for Epinephrine Spray Formulation # 20 stored at25° C. ± 2° C./60% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 3 M6 M Assay (% LC) 103.9307 102.23 99.07 97.70 Appearance Clear, Clear,Clear, Clear, Colorless Colorless Colorless Colorless Imp-F 0.19 0.160.53 1.25 2.86 epinephrone 1.35 ND BQL BQL BQL Methoxy 1.78 0.06 0.060.06 0.06 Unknown 0.21 ND ND 0.05 0.05 Impurities 0.26 ND ND ND BQL 0.70ND BQL BQL BQL 0.83 ND BQL BQL ND 0.88 BQL BQL BQL ND 1.22 ND ND ND BQL1.41 ND ND BQL BQL 1.49 ND ND ND ND 1.51 BQL ND ND ND 1.55 ND BQL BQL ND2.55 ND BQL BQL ND 2.56 ND BQL BQL ND 2.61 ND BQL BQL ND 2.72 ND ND BQLBQL 2.80 ND ND BQL ND 2.87 ND BQL ND ND 2.96 ND BQL ND ND 3.09 BQL BQLND ND 3.22 ND ND BQL ND 3.45 ND ND BQL ND 3.73 ND ND ND BQL Total 0.220.59 1.36 2.97 impurities (%)

TABLE 35 Stability Data for Epinephrine Spray Formulations # 19 storedat 25° C. ± 2° C./60% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 3M 6 M 12 M 18 M Assay (%) 101.32  99.22  100.49  98.92  100.41  98.60 Appearance Clear, Clear, Clear, Clear, Clear, Clear, Colorless ColorlessColorless Colorless Colorless Colorless % Impurity F 0.19 0.16 0.47 1.032.37 5.38 7.44 % Epinephrone 1.34 ND BQL BQL BQL BQL BQL % Methoxy 1.770.07 0.06 0.06 0.06 0.05 0.06 Unknown 0.20 ND ND 0.06 0.15 0.08 0.09Impurities (%) 0.21 ND ND ND ND 0.07 0.05 0.26 ND ND ND 0.08 0.16 0.201.06 ND ND ND ND ND 0.13 1.20 ND ND ND 0.09 0.05 0.05 2.50 ND ND ND NDBQL 0.06 Total 0.23 0.53 1.15 2.75 5.79 8.08 impurities (%)

TABLE 37 Stability Data for Epinephrine Spray Formulation # 21 stored at25° C. ± 2° C./60% ± 5% Relative Humidity RRT T = 0 1 M 2 M 3 M 4 M 6 M8 M 12 M Assay 98.20  101.02  99.07  100.13  98.45  98.45  98.45  95.12 Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear, Clear,Colorless Colorless Colorless Colorless Colorless Colorless ColorlessColorless % Impurity F 0.19 0.16 0.72 1.38 1.99 2.54 4.30 5.40 7.05 %Epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.06 0.06 0.06 0.05 0.05 0.05 Unknown 0.20 ND ND ND ND ND ND BQL BQLImpurities 0.66 ND ND ND ND ND ND ND 0.05 Total impurities 0.22 0.781.44 2.05 2.60 4.35 5.45 7.15 (%)

TABLE 38 Stability Data for Epinephrine Spray Formulations # 12 to 16stored at 40° C. ± 2° C./75% ± 5% Relative Humidity F# 12 F# 13 F# 14 F#15 F# 16 Epinephrine RRT 0 Week 2 Months 2 Months 2 Months 2 Months 2Months Assay 100.00  98.13  94.51  93.02  93.26  92.02  Appearance ClearClear Clear Clear Clear Clear % Impurity F 0.19 0.11 3.22 5.64 7.42 9.7 11.3  % Synephrine 1.26 ND ND ND ND ND ND % Epinephrone 1.36 ND BQL BQLBQL BQL BQL % Methoxy 1.90 0.07 0.06 0.06 0.06 0.06 0.06 0.22 BQL 0.160.16 0.15 0.14 0.12 0.25 ND 0.06 0.06 0.05 0.05 0.05 % Unknown 0.26 NDND BQL BQL BQL BQL Impurities 0.88 ND ND BQL BQL BQL BQL 1.21 ND 0.060.06 0.05 BQL BQL 1.34 ND BQL BQL BQL BQL BQL 1.55 ND BQL BQL BQL BQLBQL 2.57 ND 0.18 0.11 0.1  0.08 0.07 3.11 ND BQL BQL BQL BQL BQL 3.26 NDBQL BQL BQL BQL ND % Total 0.18 3.74 6.09 7.83 10.03  11.60  Impurities

TABLE 39 Stability Data for Epinephrine Spray Formulations # 17 storedat 40° C. ± 2° C./75% ± 5% Relative Humidity RRT 2 Weeks 4 Weeks 6 Weeks3 Months Physical Clear Clear Clear Clear appearance % Impurity F 0.191.02 2.03 3.01 5.11 % Epinephrone 1.36 ND ND BQL BQL % Methoxy 1.90 0.070.07 0.07 0.06 1.08 0.08 0.15 0.15 0.09 1.12 ND ND 0.15 0.15 1.21 ND BQL0.06 0.13 2.53 BQL BQL 0.05 0.15 2.58 ND ND BQL 0.06 3.04 ND ND BQL 0.06% Total 1.17 2.25 3.49 5.81 Impurities

TABLE 40 Stability Data for Epinephrine Spray Formulations #18 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT 2 Weeks 1 Month 2 MonthsAppearance Clear Clear Clear % Impurity F 0.19 0.93 2.16 3.71 %Epinephrone 1.36 ND BQL BQL % Methoxy 1.90 0.07 0.07 0.07 1.08 0.09 0.090.10 1.12 BQL 0.06 0.14 1.21 ND BQL 0.18 2.53 0.09 0.23 0.17 2.58 BQL0.08 0.07 3.04 BQL BQL 0.05 % Total Impurities 1.18 2.69 4.49

TABLE 41 Stability Data for Epinephrine Spray Formulation # 19 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT 0 Month 1 M 2M 3 M 4 M 5 M 6 M 10 M Assay 101.32  101.11  97.06  95.85  96.08  96.52 95.58  NP Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,Clear, colorless colorless colorless Light Light Light Light LightYellow Yellow Yellow Yellow Yellow Imp-F 0.19 0.16 1.92 4.25 6.42 7.207.28 7.22 7.61 epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL Methoxy1.77 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 Unknown Impurities 0.21 ND0.09 0.19 0.11 0.3  0.07 0.14 0.18 (%) 0.26 ND ND 0.14 0.21 0.31 0.320.31 0.52 0.52 ND ND ND ND BQL BQL BQL BQL 0.64 ND ND ND ND BQL ND ND ND0.79 ND ND ND BQL ND ND BQL BQL 0.88 ND BQL ND ND BQL BQL BQL BQL 1.17ND 0.06 0.07 0.05 0.09 0.08 ND ND 1.25 ND BQL BQL BQL BQL 0.07 0.07 0.071.38 ND BQL BQL BQL BQL BQL BQL BQL 1.55 ND ND ND BQL ND ND ND ND 1.68ND ND ND BQL BQL ND BQL BQL 1.73 ND ND ND BQL BQL BQL BQL BQL 1.99 ND NDND ND BQL BQL BQL BQL 2.07 ND ND ND ND BQL BQL BQL BQL 2.38 ND BQL ND NDND BQL ND ND 2.22 ND ND ND ND ND ND BQL BQL 2.44 ND ND ND ND ND ND BQLBQL 2.60 ND BQL 0.05 0.1  0.19 0.33 0.76 0.99 2.80 ND ND ND BQL ND ND NDND 2.86 ND BQL ND ND ND ND ND ND 2.98 ND BQL ND ND ND BQL ND ND 3.13 NDBQL ND ND ND ND ND ND 3.22 ND ND ND BQL ND ND ND ND 2.82 ND ND ND ND0.07 0.12 0.13 0.21 3.38 ND ND ND ND BQL ND ND ND 3.41 ND ND ND ND NDBQL ND ND 3.44 ND ND ND BQL 0.14 0.06 ND ND 3.51 ND ND ND ND ND ND 0.130.12 3.68 ND ND ND BQL BQL BQL 0.07 0.06 Total impurities (%) 0.23 2.134.76 6.95 8.36 8.39 8.89 9.82

TABLE 42 Stability Data for Epinephrine Spray Formulation # 20 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 2 M3 M 4 M 5 M 6 M Assay (%) 103.93  99.44  96.16  96.35  96.38  96.05 93.96  Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,colorless colorless colorless Light Light Light Light Yellow YellowYellow Yellow % Impurity F 0.19 0.16 2.61 5.66 7.69 6.30 7.42 7.67 %Epinephrone 1.35 ND BQL BQL BQL BQL BQL BQL % Methoxy 1.78 0.06 0.070.06 0.06 0.06 0.07 0.07 Unknown 0.21 ND 0.08 0.10 0.09 0.29 0.10 0.13Impurities (%) 0.26 ND ND 0.06 0.12 0.17 0.18 0.19 0.70 ND BQL BQL BQLBQL ND BQL 0.88 BQL BQL BQL BQL BQL BQL BQL 1.13 ND ND ND ND ND 0.08 ND1.18 ND BQL BQL BQL 0.11 ND ND 1.21 ND ND ND ND ND ND 0.06 1.34 ND ND NDND BQL BQL ND 1.36 ND ND ND BQL BQL ND BQL 1.49 ND BQL ND ND ND ND ND1.42 ND ND ND BQL ND ND ND 1.51 BQL ND ND ND ND ND ND 1.55 ND BQL BQLBQL ND ND ND 1.58 ND ND ND ND 0.09 ND ND 1.64 ND ND ND BQL ND ND ND 1.73ND ND ND ND ND BQL 0.05 1.89 ND ND ND BQL ND BQL ND 2.00 ND ND ND ND BQL0.05 0.08 2.09 ND ND ND ND ND ND 0.08 2.21 ND ND ND ND ND ND 0.08 2.39ND BQL ND ND BQL BQL ND 2.44 ND ND ND ND ND ND 0.05 2.56 ND BQL ND ND NDBQL BQL 2.61 ND BQL BQL 0.07 ND ND ND 2.71 ND ND ND ND 0.39 0.54 1.102.87 ND BQL ND BQL BQL ND ND 2.96 ND BQL ND ND ND ND BQL 3.09 BQL BQL NDND ND ND ND 3.14 ND BQL ND ND ND ND ND 3.36 ND ND ND 0.14 0.16 0.16 0.173.48 ND ND ND ND 0.22 0.04 0.19 3.55 ND ND ND BQL BQL ND BQL 3.71 ND ND0.05 ND ND 0.05 0.08 3.83 ND ND ND ND ND ND BQL 4.34 ND ND ND ND ND NDBQL Total impurities 0.22 2.76 5.93 8.17 7.79 8.69 10.00  (%)

TABLE 43 Stability Data for Epinephrine Spray Formulation # 21 stored at40° C. ± 2° C./75% ± 5% Relative Humidity Epinephrine RRT T = 0 1 M 2 M3 M 4 M 5 M 8 M 12 M Assay (%) 98.20  94.84  94.14  95.37  95.07  95.87 95.18  96.1  Appearance Clear, Clear, Clear, Clear, Clear, Clear, Clear,Clear, colorless colorless Light Light Light Light Light Light YellowYellow Yellow Yellow Yellow Yellow % Impurity F 0.19 0.16 4.43 7.96 8.208.31 7.93 8.47 8.36 % Epinephrone 1.34 ND BQL BQL BQL BQL BQL BQL BQL %Methoxy 1.77 0.06 0.06 0.06 0.06 0.05 0.09 0.05 0.05 Unknown 0.20 ND0.06 ND ND 0.11 0.11 BQL BQL Impurities (%) 0.66 ND ND ND ND ND BQL BQLBQL 0.83 ND ND ND ND ND ND 0.05 ND 1.67 ND ND ND 0.15 0.14 0.14 0.110.12 1.70 ND ND ND ND ND ND ND 0.08 1.73 ND ND ND ND ND 0.07 0.06 0.131.81 ND ND ND ND ND ND 0.08 0.05 1.82 ND ND ND ND ND ND 0.06 BQL 1.92 NDND ND ND ND ND 0.08 0.31 1.95 ND ND ND ND ND ND 0.08 0.09 2.00 ND ND NDND ND ND 0.06 0.1  2.09 ND ND ND ND ND ND 0.09 0.27 2.27 ND ND ND ND NDND ND 0.06 2.40 ND ND ND ND ND ND 0.24 0.29 2.72 ND ND ND BQL BQL BQLBQL 0.08 2.79 ND ND ND 0.17 0.18 0.26 BQL 0.57 2.84 BQL BQL ND 0.05 ND0.12 0.12 0.2  2.87 ND ND ND ND 0.2 0.13 0.12 0.62 2.96 ND ND ND ND NDND ND 0.08 2.98 ND ND ND ND ND ND ND 0.11 3.06 ND ND ND ND ND ND ND 0.143.15 ND ND ND ND ND ND ND 0.08 3.18 ND ND ND ND ND ND ND 0.06 Totalimpurities 0.22 4.55 8.02 8.63 8.99 8.85 9.67 11.85  (%)

TABLE 44 Stability Data for Epinephrine Spray Formulation # 27 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M 4 MAppearance Clear, Clear, Clear, Clear, colorless colorless Light LightYellow Yellow Assay 101.98  101.74  NP NP % Impurity F 0.19 0.16 3.363.26 3.49 % Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.08 0.08 0.20 ND 0.05 0.05 0.06 1.12 ND ND 0.09 0.05 2.14 ND ND ND 0.05Unknown 2.34 ND ND ND 0.06 (%)Impurities 2.89 ND ND ND 0.16 2.96 ND ND0.50 0.48 2.99 ND ND 0.10 0.19 3.05 ND 0.38 0.46 0.43 Total impurities0.22 3.85 4.54 5.05 (%)

TABLE 45 Stability Data for Epinephrine Spray Formulation # 28 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M 4 MAppearance Clear, Clear, Clear, Clear, colorless colorless Light LightYellow Yellow Assay 108.90  107.20  NP NP % Impurity F 0.19 0.16 1.753.15 3.61 % Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.08 0.08 Unknown 0.20 ND 0.24 0.24 0.33 Impurities (%) 0.25 ND ND 0.090.09 2.50 ND 0.10 0.25 0.83 2.96 ND ND 0.21 0.37 2.99 ND ND ND 0.05 3.05ND 0.07 0.15 0.28 3.21 ND ND ND 0.27 Total impurities 0.22 2.22 4.175.91 (%)

TABLE 46 Stability Data for Epinephrine Spray Formulation # 29 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M 4 MAppearance Clear, Clear, Clear, Clear, colorless colorless Light LightYellow Yellow Assay 101.08  102.42  NP NP % Impurity F 0.19 0.16 6.128.87 8.86 % Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.06 0.08 Unknown 0.20 ND BQL BQL BQL Impurities 0.25 ND ND ND ND 1.06ND ND ND 0.14 1.12 ND ND 0.09 0.09 1.99 ND ND 0.06 0.12 2.05 ND ND ND0.14 2.15 ND ND ND 0.08 2.34 ND ND ND 0.08 2.89 ND ND 0.11 0.23 2.96 NDND 0.45 0.47 2.99 ND ND 0.13 0.27 3.05 BQL BQL 0.40 0.43 3.20 ND ND 0.150.23 Total impurities 0.22 6.18 10.32  11.22  (%)

TABLE 47 Stability Data for Epinephrine Spray Formulation # 30 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M 4 MAppearance Clear, Clear, Clear, Clear, colorless colorless Light LightYellow Yellow Assay 106.62  107.37  NP NP % Impurity F 0.19 0.16 5.008.76 8.41 % Epinephrone 1.34 BQL BQL BQL BQL % Methoxy 1.77 0.06 0.060.09 0.08 Unknown 0.20 ND BQL 0.07 0.07 Impurities 0.25 ND ND 0.14 0.161.06 ND ND ND 0.14 1.12 ND ND 0.05 BQL 2.50 ND 0.05 0.12 0.43 2.96 ND ND0.06 0.29 2.99 ND ND ND 0.07 3.05 ND BQL 0.05 0.23 3.20 ND BQL 0.05 0.16Total impurities 0.22 5.11 9.39 10.04  (%)

TABLE 48 Stability Data for Epinephrine Spray Formulation # 31 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 101.23 115.59  NP % Impurity F 0.19 0.16 2.75 2.35 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND BQL BQL Impurities (%)1.12 ND ND 0.05 2.03 ND ND 0.05 2.79 ND ND BQL 2.86 ND ND 0.12 2.92 NDND 0.82 2.99 ND 0.05 0.14 3.05 ND 0.92 0.72 3.16 ND ND 0.08 Totalimpurities 0.22 3.78 4.42 (%)

TABLE 49 Stability Data for Epinephrine Spray Formulation # 32 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T0 1 M 3 M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 108.96 103.80  NP % Impurity F 0.19 0.16 1.89 2.50 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND 0.11 0.08 Impurities0.25 ND ND BQL 1.12 ND ND 0.07 1.19 ND ND 0.05 2.48 ND 0.16 0.50 2.92 NDND 0.49 3.00 ND 0.16 0.37 3.16 ND ND 0.16 Total impurities 0.22 2.384.31 (%)

TABLE 50 Stability Data for Epinephrine Spray Formulation # 33 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 100.05 99.36  NP % Impurity F 0.19 0.16 9.14 9.82 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.09 Unknown 0.18 ND BQL BQL Impurities (%)1.74 ND ND 0.60 1.98 ND ND 0.07 2.04 ND ND 0.07 2.32 ND ND 0.07 2.86 NDND 0.18 2.92 ND ND 0.70 2.95 ND ND 0.23 3.01 ND ND 0.62 3.16 ND ND 0.153.29 ND ND 0.05 Total impurities 0.22 9.20 12.65  (%)

TABLE 51 Stability Data for Epinephrine Spray Formulation # 34 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 1 M 3 M AppearanceClear, Clear, Clear, colorless colorless Light Yellow Assay 113.33 112.55  NP % Impurity F 0.19 0.16 6.30 9.61 % Epinephrone 1.34 BQL BQLBQL % Methoxy 1.77 0.06 0.06 0.08 Unknown 0.18 ND BQL 0.06 Impurities(%) 0.25 ND ND 0.09 1.06 ND ND 0.16 1.12 ND ND 0.07 1.32 ND ND BQL 2.32ND ND BQL 2.55 ND 0.07 0.23 2.93 ND ND 0.34 2.96 ND ND 0.07 2.98 ND ND0.08 3.02 ND 0.08 0.28 3.17 ND ND 0.08 Total impurities 0.22 6.51 11.15 (%)

TABLE 52 Stability Data for Epinephrine Spray Formulation # 35 stored at40° C. ± 2° C./75% ± 5% Relative Humidity RRT T = 0 2 M 3 M 6 M Assay101.32 83.12 91.78 100.20 Appearance Clear, Clear, Clear, Clear,colorless colorless colorless colorless % Impurity F 0.19 0.16 4.56 6.407.56 % Epinephrone 1.34 ND BQL BQL BQL % Methoxy 1.77 0.07 0.06 0.050.05 Unknown 0.20 ND ND ND 0.13 Impurities 0.21 ND 0.26 0.05 0.08 (%)0.26 ND 0.13 0.12 0.30 1.19 ND 0.06 BQL BQL 1.71 ND BQL BQL 0.05 1.95 NDND ND 0.07 2.45 ND 0.06 0.05 0.73 2.92 ND ND ND 0.19 2.95 ND ND ND 0.132.97 ND ND ND 0.16 Total 0.23 5.13 6.67 9.45 Impurities (%)

TABLE 53 Stability Data for Epinephrine Spray Formulation # 36 stored at40° C. ± 2° C./ 75% ± 5% Relative Humidity RRT T = 0 2 M 6 M Assay101.32 91.40 103.10 Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 6.81 6.90 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.06 0.05 Unknown 0.21 ND 0.09 0.07 Impurities 0.70ND BQL ND (%) 1.71 ND ND 0.07 1.92 ND ND 0.07 1.95 ND ND 0.05 2.00 ND ND0.05 2.09 ND ND 0.06 2.27 ND ND 0.05 2.41 ND ND 0.08 2.84 ND ND 0.192.90 ND ND 0.29 2.93 ND ND 0.31 2.98 ND ND 0.25 Total 0.23 6.96 8.49Impurities (%)

TABLE 54 Stability Data for Epinephrine Spray Formulation # 35 stored at25° C. ± 2° C./ 60% ± 5% Relative Humidity RRT T = 0 3 M 6 M Assay101.32 92.83 101.79 Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 1.08 2.32 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.05 0.06 Unknown 0.21 ND BQL 0.07 Impurities (%)0.26 ND ND ND 0.23 ND ND BQL 1.20 ND ND BQL 2.45 ND ND BQL Total 0.231.13 2.45 Impurities (%)

TABLE 55 Stability Data for Epinephrine Spray Formulation # 36 stored at25° C. ± 2° C./ 60% ± 5% Relative Humidity RRT T = 0 3 M 6 M Assay101.32 103.80 104.79 Appearance Clear, Clear, Clear, colorless colorlesscolorless % Impurity F 0.19 0.16 1.54 4.00 % Epinephrone 1.34 ND BQL BQL% Methoxy 1.77 0.07 0.06 0.05 Unknown 0.21 ND BQL BQL Impurities (%)0.72 ND BQL BQL 0.83 ND BQL ND 3.09 ND BQL 0.05 Total 0.23 1.60 4.10impurities (%)

All formulas exemplified in Tables 27 to 31 above, remained clearthroughout stability testing. Formulations were filled in to unit dosespray devices under nitrogen blanket, and then subjected to acceleratedstability testing at 25° C.±2° C./60%±5% and 40° C.±2° C./75%±5% withoutpouching (Formulations 12 to 18), while formulations (F #19 to 36) weresubjected to accelerated stability testing under similar conditions withpouching containing oxygen scavenges. Formulation 13, un-pouched showedimpurity F levels at 5.64% at 2M/40° C. However similar formulation 19,pouched, exhibited impurity F levels at 4.25% at 2M/40° C. Stabilitydata suggest that epinephrine spray formulations which are pouched withoxygen scavenges are more stable compare to un-pouched formulations.Both hydro-alcoholic and aqueous formulations of present invention arestable at room temperature as well as 40° C.±2° C./75%±5.

For the Epinephrine 6 mg aqueous formulation in pouches, 3.49% and 8.86%of impurity F was observed after a period of 4 months at 40° C.±2°C./75% RH±5% RH for Formulations #27 and 29 respectively. Totalimpurities for Formulations #27 and 29 were found to be 5.05% and 11.22%after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively.In the case of hydro-alcoholic formulations of the same strength inpouches, 3.61% and 8.41% of impurity F was observed after the sameperiod for formulations #28 and 30, respectively. Total impurities forFormulations #28 and 30 were found to be 5.91% and 10.04% after a periodof 4 months at 40° C.±2° C./75% RH±5% RH, respectively.

For the Epinephrine 9 mg aqueous formulation in pouches, 2.35% and 9.82%of impurity F was observed after a period of 4 months at 40° C.±2°C./75% RH±5% RH for Formulations #31 and 33 respectively. Totalimpurities for formulations #31 and 33 were found to be 4.42% and 12.65%after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively.In the case of hydro-alcoholic formulations of the same strength inpouches, 2.50% and 9.61% of impurity F was observed after the sameperiod for Formulations #32 and 34. Total impurities for Formulations#32 and 34 were found to be 4.31% and 11.15% after a period of 4 monthsat 40° C.±2° C./75% RH±5% RH, respectively.

Example 6. Mini-pig Pharmacokinetic Data for Epinephrine Formulations

Protocol design was a single-dose crossover study. Five healthy maleYucatan mini-pigs weighing approximately eighty to ninety-five kilogramseach were administered epinephrine formulations. The minipigs werefasted overnight till four hours' post administration. Each dosing wasfollowed by a washout period of at least one-week. Blood samples weretaken prior to administration and 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5,2, 4, and 24 hours' post dose. Minipig plasma samples were measured forepinephrine concentrations via liquid chromatography-tandem massspectrometry.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to reach C_(max) (T_(max)), andarea under the concentration-time curve from time-zero to 24 hourspostdose (AUC_(0-24 h)).

The pharmacokinetic behavior of epinephrine formulations was evaluated.At 5 minutes after a single-dose intramuscular (IM) administration ofepinephrine in minipigs, the geometric mean plasma concentration ofepinephrine was 0.046 ng/mL. When epinephrine was formulated in #M1 andadministered intranasally, a more rapid absorption of epinephrine wasobserved. Specifically, #M1 showed a geometric mean epinephrine plasmaconcentration of 0.26 ng/mL at 5 minutes postdose. It was also notedthat a plasma concentration of 0.41 ng/mL was achieved as early as 2minutes after an intranasal administration of #M1. In addition, #M1showed a geometric mean Cmax of 1.01 ng/mL and a geometric meanAUC_(0-24 h) of 161.0 ng*min/L.

TABLE 56 Epinephrine Formulations for Minipig Dosing Formulation #M1Epinephrine base 3.25 Dilute Hydrochloric acid 0.5N 36.2 BenzalkoniumChloride 0.01 Ethanol 40 Propylene Glycol 5 Sodium Bisulfite 0.15 EDTA0.05 Water 15.34 Total 100 Components: % w/w

TABLE 57 Plasma concentrations for epinephrine after administration toYucatan minipigs under fasted conditions. Formulation IM solution #M1Route of administration IM Intranasal Dose per animal (mg) 0.3 6Concentration @ 2 min (ng/mL) 0.036 0.41 Concentration @ 5 min (ng/mL)0.046 0.26 Concentration @ 10 min (ng/mL) 0.073 0.31 Concentration @ 15min (ng/mL) 0.103 0.17 Concentration @ 30 min (ng/mL) 0.100 0.19 T_(max)(min) 90 5 C_(max) (ng/mL) 0.25 1.01 AUC_(0-24h) (ng * min/mL) 173.7161.0 Plasma concentration: geometric mean T_(max): median value C_(max)and AUC_(0-24h): geometric mean

Example 7. Rabbit Pharmacokinetic Data for Epinephrine Formulations

Protocol design was a single-dose non-crossover study. Pharmacokineticsof a number of epinephrine formulations were evaluated in healthy maleNew Zealand white rabbits weighing approximately two to three kilograms.For dosing of each formulation, five or six rabbits were used. Therabbits were fasted overnight till four hours' post administration.Blood samples were taken prior to administration and 5, 10, 15, 20, 30,40 min, 1, 1.5, 2, 4, and 5 hours' post dose. Rabbit plasma samples weremeasured for epinephrine concentrations via liquid chromatography-tandemmass spectrometry.

Formulation #R1-#R8 were provided in Table 43 and 44. Formulation #R9existed as a spray-dried powder of epinephrine bitartrate salt. For theevaluation of #R9, approximately 21.83 mg of powder was dosed to eachanimal, as an equivalent dose of 12 mg epinephrine.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to reach C_(max) (T_(max)), andarea under the concentration-time curve from time-zero to 24 hourspostdose (AUC_(0-24 h)).

The pharmacokinetic behavior of epinephrine formulations was evaluated.At 5 minutes after a single-dose IM administration of epinephrine inrabbits, the mean plasma concentration of epinephrine was 0.988 ng/mL.In comparison, a sublingual administration of #R9 enabled a similarabsorption of epinephrine in the early phase. Specifically, #R9 showed amean epinephrine plasma concentration of 0.0.814 ng/mL at 5 minutespostdose. It was also noted that a plasma concentration of 0.713 ng/mLwas achieved at 5 minutes after a sublingual administration of #R6. Inaddition, #R9 showed a geometric mean Cmax of 7.0 ng/mL and a geometricmean AUC0-24 h of 1050.1 ng*min/L.

TABLE 58 Epinephrine Formulations for Rabbit Dosing Formulation #R1 #R2#R3 #R4 #R5 Epinephrine base 0 0.006 3.025 3.243 3.243 DiluteHydrochloric 0.3 0.5 33.27 36.2 36.2 Acid 0.5N Dehydrated Alcohol 40 40Menthol 1 1 Sucralose 0.5 0.5 0.5 0.5 Propylene Glycol 5 5 SodiumBisulfite 0.2 0.01 0.2 0.3 0.3 Edetate Disodium 0.05 0.05 0.05 0.05(EDTA) Water USP 98.45 98.584 62.455 13.707 13.707 Total 100 100 100 100100 Components: % w/w

TABLE 59 Additional Epinephrine Formulations for Rabbit DosingFormulation #R6 #R7 #R8 Epinephrine base 6.648 12.88 12.88 DiluteHydrochloric Acid 1.5N 24.6 Dilute Hydrochloric Acid 3N 24.2 24.2Dehydrated Alcohol 40 40 40 Menthol 0.5 0.5 0.5 Sucralose 0.5 0.5 0.5Propylene Glycol 5 5 5 Sodium Bisulfite 0.6 0.6 0.6 Edetate Disodium(EDTA) 0.1 0.1 0.1 Water USP 21.552 15.72 15.72 Caprylic acid 0.5 Capricacid 0.5 Total 100 100 100 Components: % w/w

TABLE 60 Plasma concentrations for epinephrine after administration torabbits under fasted conditions. Formulation #R1 #R2 #R3 #R4 #R5 Routeof administration SL IM SL SL SL Dose per animal (mg) 0 0.03 3 3 6Concentration @ 0.020 0.99 0.28 0.19 0.11 5 min (ng/mL) Concentration @0.011 0.83 0.24 0.32 0.35 10 min (ng/mL) Concentration @ 0.014 0.79 0.490.55 0.86 15 min (ng/mL) Concentration @ 0.012 0.73 0.44 1.24 1.94 30min (ng/mL) T_(max) (min) 300 15 240 90 90 C_(max) (ng/mL) 0.05 1.1 1.32.9 6.3 AUC_(0-24h) (ng * min/mL) 6.7 96.7 217.0 537.1 956.8 Plasmaconcentration: mean T_(max): median value C_(max) and AUC_(0-24h):geometric mean IM denotes intramuscular, SL denotes sublingual

TABLE 61 Plasma concentrations for epinephrine after administration torabbits under fasted conditions. Formulation #R6 #R7 #R8 #R9 Route ofadministration SL SL SL SL Dose per animal (mg) 6 12 12 12 Concentration@ 5 min (ng/mL) 0.71 0.28 0.12 0.81 Concentration @ 10 min (ng/mL) 0.370.46 0.17 1.10 Concentration @ 15 min (ng/mL) 0.51 0.83 0.53 1.40Concentration @ 30 min (ng/mL) 0.93 2.75 3.34 3.57 T_(max) (min) 120 120180 65 C_(max) (ng/mL) 3.1 6.0 14.3 7.0 AUC_(0-24h) (ng * min/mL) 482.2867.0 2145.1 1050.1 Plasma concentration: mean T_(max): median valueC_(max) and AUC_(0-24h): geometric mean

Example 8. Intranasal Administration of Epinephrine Spray FormulationsMethods

TABLE 62 Clinical Formulations Formulation #C1 #C2 Epinephrine Base2.962 3.178 Hydrochloric Acid 0.5N 32.93 35.471 Edetate DisodiumDihydrate 0.05 0.05 Sodium Bisulfite 0.15 0.15 Benzalkonium Chloride0.01 0.01 Dehydrated alcohol — 40 Sodium Chloride 0.6 — Water 63.29816.141 Components: % w/w

Protocol design was a Phase I, proof-of-concept, single-dose open-label,5-treatment, crossover study to assess the bioavailability of intranasalformulations in adults with seasonal allergies. The study assessed thebioavailability of a single dose 3 milligrams and 6 milligrams dose ofepinephrine in a formulation of the present invention to a single 0.3milligram intramuscular dose of epinephrine via an EpiPen® (0.3milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligramssodium metabisulfite, hydrochloric acid to adjust pH, and water forinjection). 50 subjects were randomly assigned to one of five groupsincluding 3 milligram intranasal dose of an aqueous formulation of thepresent invention, 3 milligram intranasal dose of a hydro-alcoholicformulation of the present invention, 6 milligram intranasal dose of anaqueous formulation of the present invention, 6 milligram intranasaldose of a hydro-alcoholic formulation of the present invention and a 0.3milligram intramuscular dose administered over 4 periods with periods 1and 2 administered in the absence of allergen and periods 3 and 4 in thepresence of an allergen that caused seasonal allergies in the subject.Plasma concentrations were taken at −60, −30, 0, 1, 3, 5, 10, 15, 20,30, 40, 50, 60, 75, 90, 120, 180, 240 and 360 minutes post-dose.

Results

TABLE 63 Pharmacokinetic profile prior to allergen exposure FormulationT_(max) (Mean) C_(max) (pg/mL) AUC_(last) (h * pg/mL) AUC_(inf) (h *pg/mL) Aqueous 0.376 (0.05-1.25) Mean 256 (23.4-1260) Mean 231(31.4-958) Mean 377 (37.9-1860) GeoMean 149 GeoMean 153 GeoMean 206Hydro- 0.41 (0.05-2.0) Mean 419 (77.6-1110) Mean 596 (30.7-3520) Mean727 (31.2-4150) alcoholic GeoMean 314 GeoMean 317 GeoMean 385 Epipen ®0.281 (0.05-0.833) Mean 511 (148-1160) Mean 307 (89.1-698) Mean 329(91.4-749) GeoMean 429 GeoMean 255 GeoMean 273

TABLE 64 Pharmacokinetic profile after allergen exposure FormulationT_(max) (Mean) C_(max) (pg/mL) AUC_(last) (h * pg/mL) AUC_(inf) (h *pg/mL) Aqueous 0.13 (0.017-0.667) Mean 418 (78.5-1900). Mean 231(76.1-573). Mean 273 (94.9-620). GeoMean 268 GeoMean 197 GeoMean 237Hydro- 0.12 (0.017-0.667) Mean 639 (60.6-3150). Mean 429 (51.8-963).Mean 497 (52-1100). alcoholic GeoMean 447 GeoMean- GeoMean 376 Epipen ®0.225 (0.05-0.667) Mean 649 (201-1750). Mean 317 (125-557). Mean 362(166-706). GeoMean 517 GeoMean 286 GeoMean 326

TABLE 65 Early Epinephrine plasma concentrations Before Allergen TimeMean Exposure (Minutes) (Min-Max) pg/ml Aqueous 1 47.8 ( 0-264) 3 154(0-749) 5 171 (9.17-844) 10 198 (9.37-1260) Hydro-alcoholic 1 84 (0-353)3 244 (6.73-933) 5 250 (2.13-1030) 10 200 (34.5-718) After Allergen TimeMean Exposure (Minutes) (Min-Max) pg/ml Aqueous 1 174 (1.77-1390) 3 353(28.2-1900) 5 288 (31.3-1040) 10 183 (36.2-461) Hydro-alcoholic 1 290(10.5-1300) 3 581 (42.3-3150) 5 398 (43.5-1340) 10 257 (20.6-692)

As seen in Tables 63-65 and FIGS. 1-3 , subjects administered 6milligrams of epinephrine in a hydroalcoholic formulation of the presentinvention in the presence of an allergen had a higher C_(max) than allother cohorts. Further, as seen in FIGS. 1-3 , subjects administered 0.3milligrams of epinephrine as an intramuscular injection in absence of anallergen had a higher C_(max) than all other cohorts in the absence ofan allergen. Among subjects receiving either the aqueous or thehydroalcoholic formulations the subjects receiving the hydroalcoholicformulations had a higher C_(max) across the entire sampling time thanthose receiving the aqueous formulation both in the absence and presenceof an allergen. Epinephrine plasma concentrations were greater than 100pg/mL up to 30 min post dose for all formulations. Further, epinephrineplasma concentration were greater than 100 pg/mL in less than 5 minutespost dose for all formulations of the present invention regardless ofexposure to an allergen. Subjects administered the hydroalcoholicformulation had higher exposure in the entire sampling times for up to 6hours compared to the aqueous formulation.

In conclusion, the bioavailability of intranasal formulations of thepresent invention is as good or better than that of the intramuscularinjection both in subject that are and are not experiencing seasonalallergies.

Example 9. Comparison of Intranasal Formulations of the Invention withEpipen® and IM Adrenalin Methods

This was a single-dose, open-label, randomized, four-treatment, four-waycrossover study to assess the pharmacokinetics of two test formulationsof hydro-alcoholic Epinephrine Nasal Spray containing 7 mg (2 sprays ofComposition #37) and 8.5 mg (2 sprays of Composition #38) epinephrine incomparison with reference formulations of Epinephrine IM Injection,EpiPen® (0.30 mg administered intra muscularly), and Epinephrine IMInjection, Adrenalin® (0.50 mg administered intramuscularly; Adrenalin®contains 1.0 milligrams epinephrine, 6.15 milligrams sodium chloride,0.457 milligrams sodium metabisulfite, 0.920 milligrams sodiumhydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams disodiumedetate dihydrate, hydrochloric acid to adjust pH, milligramschlorobutanol and water for injection). Each dose of study treatment wasseparated by a washout period of 24 hours. Healthy volunteer subjectsreceived hydro-alcoholic Epinephrine Nasal Spray (7 mg and 8.5 mg) andEpinephrine IM Injection (EpiPen® [0.30 mg] and Adrenalin® [0.50 mg]),following an overnight fast of at least 10 hours.

This study consisted of five periods: a Screening Period and fourTreatment Periods. During screening (Day -28 to Day -1), subjects signedthe informed consent and then underwent determination of eligibility.Based on successful completion of the screening process, approximately48 subjects were enrolled. Subjects received a single dose of each testformulation and a single dose of each reference formulation administeredon Day 1 Period 1, Day 2 Period 2, Day 3 Period 3, and Day 4 Period 4,depending upon treatment sequence assignment. Subjects were confinedbefore dosing to ensure adherence to the 10 hour fast and remainedconfined until all study procedures are completed on Day 5. No food wasallowed until at least 4 hours after each dose administration. No waterwas consumed from 1 hour prior until 1 hour after each doseadministration. Meals were provided at scheduled times. Blood samplesfor pharmacokinetic (PK) analyses was collected prior to and at multipletimes following each dose of study drug. Safety and tolerability wasassessed throughout the study.

Pharmacokinetics

Sampling times: A total of 288 mL (72×4 mL samples) of blood wascollected for pharmacokinetic analysis from each subject. Blood samples(1×4 mL) for epinephrine analysis was collected in Vacutainer tubescontaining K₂-EDTA as a preservative at −60 and −30 minutes, 0 hour(pre-dose), 1, 3, 5, 7, 10, 15, 20, 30, and 45 minutes; and at 1, 1.5,2, 3, 4, and 6 hours post dose (18 time points) in each study period.The pre-dose blood sample was collected within 60 minutes prior to eachdose of study drug.

Bioanalytical method: Plasma concentrations of epinephrine was analyzedusing a validated liquid chromatography coupled with tandem massspectrometry (LC/MS/MS) assay with a lower limit of quantification(LLOQ) of 10.0 pg/mL.

PK parameters: Plasma concentrations of epinephrine (with and withoutbaseline-correction) were used to determine the following PK parametersusing noncompartmental PK analysis (NCA):

-   -   1. Maximum plasma concentration observed (C_(max)),    -   2. Time to reach maximum plasma concentration (t_(max)),    -   3. Area under the curve from time 0 to the last measured        concentration (AUC_(last)),    -   4. Area under the curve extrapolated to infinity (AUC_(0-inf)),    -   5. The time prior to the first measurable (non-zero)        concentration (t_(lag)),    -   6. Terminal elimination half-life (t_(1/2)),    -   7. The last quantifiable concentration (Clast), and time        corresponding this concentration (t_(last)),    -   8. Apparent total body clearance after extravascular        administration (CL/F),    -   9. Apparent volume of distribution in the terminal phase (Vz/F),        and    -   10. Relative bioavailability of epinephrine for test formulation        compared to reference formulation (Frel).

Baseline-correction was performed by subtracting the mean of epinephrineconcentrations at −1, −0.5, and 0 h from each post-dose concentration.Baseline-corrected concentrations that are less than 0 will be set to 0pg/mL.

Results

TABLE 66 Mean plasma concentration after administration of nasalcompositions #37 and #38, Epipen ® and intramuscular adrenalin BC-MeanPlasma Composition #37 Composition #38 Epipen ® IM Adrenalin IM Conc(7.0 mg) (8.5 mg) (0.3 mg) (0.5 mg) h Mean CV (%) Mean CV (%) Mean CV(%) Mean CV (%) 0.0000 0 0 0 0 0 0 0 0 0.0167 176 147 217 188 41.2 13139.6 177 0.0500 768 178 860 187 444 143 222 158 0.0833 663 167 1020 189502 86.6 288 110 0.1167 623 158 1000 188 416 78.7 246 87.8 0.1667 566157 965 193 346 98.6 196 70.8 0.2500 535 142 863 156 303 63.5 197 75.40.3333 455 129 749 131 314 50.1 251 73.3 0.5000 389 105 580 104 288 45.6391 65.9 0.7500 283 95.8 440 99.0 164 56.7 438 59.9 1.0 251 108 356 98.0104 57.9 310 48.1 1.5 175 109 249 81.8 44.1 76.2 130 58.9 2.0 123 97.0199 85.7 30.7 79.8 65.8 54.0 3.0 73.8 90.2 117 79.2 17.7 103 34.4 66.64.0 54.6 140 72.0 94.5 18.1 93.8 37.3 68.7 6.0 14.5 176 33.3 113 6.10156 18.3 87.6

TABLE 67 Pharmacokinetic parameters after administration of nasalcompositions #37 and #38, Epipen ® and intramuscular adrenalinComposition #37 Composition #38 Epipen ® IM Adrenalin IM (7.0 mg)(8.5mg) (0.3mg) (0.5mg) N 48 49 49 49 C_(max) (pg/mL) 1040 ± 1380 1420 ±2080 768 ± 585 602 ±326 (133) [536] (146) [686] (76.2) [617] (54.1)[531] t_(max) ^(b) (h) 0.167 (0.0167-4.0) 0.267 (0.0167-3.0) 0.0833(0.05-1.0) 0.550 (0.05-1.0) AUC_(last) 785 ± 795 1200 ± 1040 357 ± 119598 ± 229 (pg · h/mL) (101) [521] (86.7) [813] (33.4) [338] (38.3) [555]AUC_(0-inf) 960 ± 594 1440 ± 1160 365 ± 118 685 ± 281 (pg · h/mL) (61.9)[828] (80.6) [1030] (32.3) [346] (41.0) [627] t_(1/2) (h) 1.20 ± 0.5421.51 ± 0.914 0.979 ± 0.586 1.99 ± 1.76 (45.3) [1.09] (60.7) [1.31](59.9) [0.833] (88.3) [1.37] Note: C_(max), AUC and t_(1/2) valuesrepresent Mean ± SD (CV) [GeoMean]

TABLE 68 Baseline-adjusted Epinephrine Plasma Concentrations and TheirRatios to EpiPen ® 0.3 mg IM Injection at Early Times Through 60 MinutesPost-dose Compositions #37 Composition #38 Adrenalin ® 0.5 mg (7.0 mg)[N = 48] (8.5 mg) [N = 49] EpiPen ® 0.3 mg IM Injection (N = 49) Time inRatio to Ratio to IM Injection [N = 49] Ratio to Minutes Conc* EpiPenConc* EpiPen Conc* Conc* EpiPen 1 176 (147) 4.3 217 (188) 5.3 41.2 (131)39.6 (177) 1.0 3 768 (178) 1.7 860 (187) 1.9 444 (143) 222 (158) 0.5 5663 (167) 1.3 1020 (189) 2    502 (86.6) 288 (110) 0.6 7 623 (158) 1.51000 (188) 2.4 416 (78.7) 246 (87.8) 0.6 10 566 (157) 1.6 965 (193) 2.8346 (98.6) 196 (70.8) 0.6 15 535 (142) 1.8 863 (156) 2.8 303 (63.5) 197(75.4) 0.7 20 455 (129) 1.4 749 (131) 2.4 314 (50.1) 251 (73.3) 0.8 30389 (105) 1.4 580 (104) 2   288 391 (65.9) 1.4 45 283 (95.8) 1.7 440(99.0) 2.7 164 (56.7) 438 (59.9) 2.7 60 251 (108) 2.4 356 (98.0) 3.4 104(57.9) 310 (48.13) 3   *Mean (CV %) plasma concentration in pg/Ml Conc =Concentration

TABLE 69 Epinephrine Baseline-Adjusted Partial Areas Under the PlasmaEpinephrine Concentration Versus Time Curve and Their Ratios to EpiPen0.3 mg IM Injection at Early Times Through 60 Minutes Post-doseCompositions #37 Composition #38 EpiPen ® 0.3 mg Adrenalin ® 0.5 mg (7.0mg) [N = 48] (8.5 mg) [N = 49] IM Injection IM Injection (N = 49) Ratioto Ratio to [N = 49] Ratio to AUC* EpiPen AUC* EpiPen AUC* AUC* EpiPenAUC₀₋₀₀₁₇ 1.50 (150) 4.2 1.80 (195) 5   0.358 (130) 0.324 (180) 0.9AUC_(0-0.05) 16.8 (153) 2   19.1 (182) 2.3 8.44 (131) 4.54 (141) 0.5AUC_(0-0.083) 39.8 (163) 1.7 49.8 (180) 2.1 23.9 (112) 12.8 (129) 0.5AUC_(0-0.117) 61.1 (161.0) 1.6 83.9 (179) 2.1 39.3 (94.1) 21.8 (113) 0.6AUC_(0-0.167) 90.4 (156) 1.6 133 (180) 2.3 58.1 (82) 32.7 (98.6) 0.6AUC_(0-0.25) 136 (148) 1.6 208 (176.0) 2.5 84.7 (72.3) 48.8 (85.6) 0.6AUC_(0-0.33) 175 (143) 1.6 272 (167) 2.5 109 (64) 66.4 (77.4) 0.6AUC_(0-0.5) 246 (132.0) 1.5 386 (147) 2.4 160 (51.0) 120 (65.6) 0.8AUC_(0-0.75) 329 (120) 1.5 513 (129) 2.4 214 (42.2) 223 (57.6) 1  AUC₀₋₁ 395 (112) 1.6 611 (120) 2.5 247 (38.7) 315 (50.5) 1.3 *Mean (CV%) area under the curve (AUC) between time 0 and t, h*pg/mL

As can be seen in Table 66, intranasal administration of compositions#37 and #38 resulted in higher plasma concentrations 5 minutes (0.0833hours) after administration than either Epipen® or intramuscularadrenalin. In fact, the 8.5 mg dose of composition #38 resulted in morethan twice the plasma concentration of either Epipen® or intramuscularadrenalin. Plasma concentrations of epinephrine remained higher insubjects administered compositions #37 or #38 than Epipen® orintramuscular adrenalin for 6 hours following administration.

As can be seen in Table 67, intranasal administration of compositions#37 and #38 resulted in higher C_(max), AUC_(last) and AUC_(0-inf) thaneither Epipen® or intramuscular adrenalin. In fact, administration ofcompositions #37 and #38 resulted in 1.4 and 1.8 times greater C_(max)than Epipen®.

As seen in Table 68, intranasal administration of compositions #37 and#38 resulted in much higher ratios of epinephrine plasma concentrationscompared to EpiPen® than did Adrenalin® IM injections. In fact,administration of compositions #37 and #38 resulted in 4.3- and5.3-times higher epinephrine plasma concentration after 1 minutecompared to EpiPen®.

As seen in Table 69, intranasal administration of compositions #37 and#38 resulted in much higher ratios of epinephrine AUC compared toEpiPen® than did Adrenalin® IM injections. In fact, administration ofcompositions #37 and #38 resulted in 4.2- and 5-times higher epinephrineAUC after 1 minute compared to EpiPen®.

What we claim is:
 1. An epinephrine spray solution comprising from about0.1% w/w to about 15% w/w epinephrine or a salt thereof and from 0.9% to80% w/w water, wherein w/w denotes weight by weight of the solution andwherein the solution has a pH from about 2 to about
 7. 2. The solutionof claim 1, further comprising from about 1% w/w to about 99% w/w of asolvent selected from the group consisting of ethanol, glycerin,propylene glycol, polyethylene glycol 400 and a combination thereof. 3.The solution of claim 1, further comprising from about 0.1% w/w to about60% w/w of at least one acid.
 4. The solution of claim 1, wherein thesolution does not contain sorbitol.
 5. The solution of claim 2, whereinthe solvent comprises from about 2% w/w to about 60% w/w ethanol.
 6. Thesolution of claim 1, wherein the at least one acid is dilutedhydrochloric acid.
 7. The solution of claim 1, wherein the epinephrinesalts are selected from the group consisting of citrate, hydrochloride,halide, sulfate, bitartrate, tartrate, phosphate, acetate, malate,maleate, succinate, ascorbate, carbonate, mesylate and lactate.
 8. Thesolution of claim 1, further comprising a stabilizer or chelating agentselected from the group consisting of butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodiumascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite,ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteinehydrochloride, benzalkonium chloride (BKC), citric acid, edetatedisodium dihydrate (EDTA), sodium citrate, propyl gallate,8-hydroxyquinoline, boric acid, histidine and combinations thereof. 9.The solution of claim 8, wherein the stabilizer or chelating agentcomprises EDTA at a concentration from about 0.005% w/w to about 0.5%w/w.
 10. The solution of claim 8, wherein the stabilizer comprisessodium bisulfite or sodium metabisulfite or a combination thereof at aconcentration from about 0.005% w/w to about 5% w/w.
 11. The solution ofclaim 8, wherein the stabilizer or chelating agent comprises BKC at aconcentration from about 0.005% to about 0.5% w/w.
 12. A method oftreating anaphylaxis comprising administering the solution of claim 1 toa subject in need thereof.
 13. The method of claim 12, wherein thesubject is suffering from nasal congestion.
 14. The method of claim 12,wherein administration occurs via an intranasal route.
 15. The method ofclaim 12, wherein administration occurs via a multi-dose device thatdelivers more than one dose of the solution of claim 1 to the subject.16. The method of claim 15, wherein the multi-dose device is a bi-dosedevice that delivers two doses of the solution of claim 1 to thesubject.